Complementary and Alternative Medicine

Number: 0388

Policy

Aetna considers alternative medicine interventions medically necessary if they are supported by adequate evidence of safety and effectiveness in the peer-reviewed published medical literature.  The following are some of the alternative medicine interventions that Aetna considers medically necessary for properly selected members, subject to applicable benefit plan limitations and exclusions:

• Acupuncture - see CPB 0135 - Acupuncture 
• Biofeedback - see CPB 0132 - Biofeedback 
• Chelation therapy - see CPB 0234 - Chelation Therapy
• Chiropractic services - see CPB 0107 - Chiropractic Services  
• Electrical stimulation - see CPB 0011 - Electrical Stimulation for Pain.

Aetna considers the following alternative medicine interventions experimental and investigational, because there is inadequate evidence in the peer-reviewed published medical literature of their effectiveness:

Footnotes for functional intracellular analysis* Functional intracellular analysis is also known as essential metabolic analysis, intracellular micronutrient analysis, leukocyte nutrient analysis, as well as micronutrient testing.

Footnotes for Glutathione** Glutathione infusion is considered experimental and investigational for anxiety, chemotherapy-induced neuropathy, chronic fatigue syndrome, common variable immune deficiency, contrast media-induced nephropathy, depression, and functional diarrhea.

Aetna does not cover medical marijuana because it is not an FDA-approved prescription medication. Please check benefit plan descriptions for details.

Aetna considers Airrosti (Applied Integration for the Rapid Recovery of Soft Tissue Injuries) and augmented soft tissue mobilization (ASTM) as proven non-preferentially for physical therapy, as there is a lack of reliable published evidence that Airrosti or ASTM is superior to other physical therapy providers.

Note: Aetna standard benefit plans exclude coverage of nutritional supplements.  Please check benefit plan descriptions.  Nutritional supplements that would be excluded under these standard benefit plans include bilberry, black cohosh, bovine cartilage, cat’s claw, Coriolus versicolor mushroom, Echinacea, fish oil, Gikgo biloba, glucosamine, kava, milk thistle, saw palmetto, shark cartilage, St. John’s wort, valerian, and yohimbine (not an all-inclusive list).

Background

"Alternative medicine" is a term used for a broad range of treatments and practices that have not gained wide acceptance in the traditional medical community and so are not considered standard medical treatment.  Other terms used to describe such procedures include "holistic", "unconventional", and "complementary".

Alternative therapies are based on no common or consistent ideology, therapy of illness, or treatment.  They derive from a variety of sources: ethnic and folk traditions, mainstream medical practices, established religions or semi-religious cults, philosophies or metaphysical movements, and health-and-wellness groups.  The National Institutes of Health's Office of Alternative Medicine classified alternative therapies into the following 7 categories:

• Alternative systems of medical practice - use of medicine from another culture (e.g., Ayurvedia, Chinese medicine) 
• Bioelectromagnetic therapies - use of electrical currents or magnetic fields to promote healing (e.g., bone repair, electroacupuncture)
• Diet and nutrition - use of specific foods, vitamins, and minerals to prevent illness and to treat disease 
• Herbal medicine - use of plants as medicine 
• Manual healing methods - use of the hands to promote healing (e.g., massage, chiropractic)
• Mind-body interventions - use of the mind to enhance health (e.g., hypnosis, meditation, yoga)
• Pharmacologic and biologic treatments - use of various substances (e.g., drugs, serums) to treat specific medical problems.

The efficacy of various alternative medicine regimens is generally unproven, and some alternative therapies have been shown to be ineffective or even harmful. 

Active release technique (ART) is a patented soft tissue system that treats problems with muscles, tendons, ligaments, fascia and nerves (e.g., headaches, back pain, carpal tunnel syndrome, shin splints, shoulder pain, sciatica, plantar fasciitis, knee problems, and tennis elbow).  These conditions have one important commonality - they often result from injury to over-used muscles.  Each ART session is a combination of examination and treatment.  The ART provider uses his/her hands to evaluate the texture, tightness and movement of muscles, fascia, tendons, ligaments and nerves.  Abnormal tissues are treated by combining precisely directed tension with very specific patient movements.  These treatment protocols - over 500 specific moves - are unique to ART.  They supposedly allow providers to identify and correct the specific problems that are affecting each individual patient.  Active release technique is similar to some massage techniques, albeit more aggressive.

While ART may be utilized by some chiropractors, it is different from conventional chiropractic manipulation.  Furthermore, Drover et al (2004) reported that ART protocols did not reduce inhibition or increase strength in the quadriceps muscles of athletes with anterior knee pain.  Further study is required.

Airrosti (applied integration for the rapid recovery of soft tissue injuries) centers are primarily concentrated in Texas, and focus on management of soft tissue injuries and chronic pain.  Airrosti uses standard physical therapy modalities.  There is a lack of published scientific evidence that Airrosti is superior to other physical therapy providers.

Bioidentical hormones (e.g., estrogen, testosterone, dehydroepiandrosterone [DHEA], etc.) are manufactured to have the same molecular structure as the hormones made by one's own body, and have been used in conjunction with laboratory tests of salivary hormone levels.  These preparations can be custom-made for patients according to a physician's specifications.  Based on test results, providers prescribe dosages of bioidentical hormones that are compounded at a pharmacy.  Proponents of bioidentical hormones state that they are better than synthetic hormones in that they are "natural" and that they are more easily metabolized by the body, minimizing side effects.  They state that synthetic hormones are stronger than bioidentical hormones and often produce intolerable side effects.

According to a committee opinion by the American College of Obstetricians and Gynecologists (ACOG, 2005), there is no scientific evidence to support claims of increased safety or effectiveness for individualized estrogen or progesterone regimens prepared by compounding pharmacies.  Furthermore, hormone therapy does not belong to a class of drugs with an indication for individualized dosing.  The opinion by ACOG also pointed out that salivary hormone level testing used by proponents to 'tailor' this therapy isn't meaningful because salivary hormone levels vary within each woman depending on her diet, the time of day, the specific hormone being tested, and other variables.

According to ACOG, most compounded products, including bioidentical hormones, have not undergone rigorous clinical testing for either safety or efficacy.  Also, there are concerns regarding the purity, potency, and quality of compounded products.  In 2001, the United States Food and Drug Administration (FDA) analyzed a variety of 29 product samples from 12 compounding pharmacies and found that 34 % of them failed one or more standard quality tests.  Additionally, 9 of the 10 failing products failed assay or potency tests, with all containing less of the active ingredient than expected.  In contrast, the testing failure rate for FDA-approved drug therapies is less than 2 %.  The FDA requires manufacturers of FDA-approved products that contain estrogen and progestogen to include a black box warning that reflects the findings of the Women's Health Initiative.  However, compounded products, including bioidentical hormones, are not approved by the FDA and therefore, compounding pharmacies are exempt from including warnings and contraindications required by the FDA in class labeling for hormone therapy.

Given the lack of well-designed and well-conducted clinical trials of these compounded hormones, ACOG recommended that all of them should be considered to have the same safety issues as those hormone products that are approved by the FDA and may also have additional risks unique to the compounding process.

In a position statement, the Endocrine Society (2006) stated that it is concerned that patients are receiving potentially misleading or false information about the benefits and risks of bioidentical hormones.  It stated that the efficacy of bioidentical hormone therapy is unproven.

There are few, if any, carefully designed studies on the use of hypnotherapy in the treatment of mental health problems (Kirsch et al, 1995; Mamtani and Cimino, 2002; Fromm and Shor, 2006).  Based on the current research literature, there is insufficient evidence to support the use of hypnosis in the treatment of psychiatric and psychological disorders, such as depression and anxiety.  Furthermore, there also has been no experimental validation of the effectiveness of hypnosis in controlling the symptoms of attention deficit disorder (Baumgartel, 1999).

Proponents of neural therapy believe that

1. the nervous system influences all bodily functions,
2. energy flows freely through the body of a healthy person, and
3. illness and chronic pain disrupt this flow of energy. 

It involves the injection of anesthetics into various places of the body to eliminate pain and cure illness.  This method is not to be confused with nerve blocks and local anesthesia used in conventional medicine.  In neural therapy, anesthetics such as lidocaine and procaine, are injected into areas of the body that may be located far from the pain source.  These injections are meant to eliminate "interference fields" and restore the body's natural energy flow.  The injections may be given into nerves, acupuncture points, glands, scars, and trigger points.  A course of treatment may involve 1 or more injections spread over several weeks.  A few practitioners use electrical current and lasers instead of injected drugs.  Research into neural therapy has been done mainly in Germany where it is widely used; however, there is insufficient evidence on the effectiveness of neural therapy for pain management or for any other health problems (American Cancer Society, 2007).

Griffiths et al (1998) examined the the role of the T-lymphocytic cell cycle as well as an autogenous lymphocytic factor (ALF) in the diagnosis and regulation of immunological incompetence.  A total of 315 individuals (chemically sensitive immunocompromised patients, n = 290; controls, n = 25) were investigated.  Each patient had been on a standard therapy of avoidance of pollutants, nutritional supplementation, and injections of antigens for foods, and biological inhalants, but did not achieve immunological competence.  Peripheral lymphocytes were collected and DNA histograms were constructed.  The flow cytometer was used to evaluate the cell cycle, hematological, and other immunological profiles.  From the other portion of the blood specimen, lymphocytes were propagated in-vitro, harvested, and a lysate, termed ALF, was prepared.  When treated with ALF, 88 % of these individuals showed a significant (p < 0.001) clinical improvement that correlated with laboratory findings, involving regulation of abnormal cell cycles, increase in total lymphocytes and subsets T4, T8, (p < 0.05) and cell-mediated immunity (CMI) response (p < 0.001).  The authors stated that ALF presumably acts as a biological response modifier.  More research is needed to determine the role of ALF in clinical medicine.

The Juvent 1000 Dynamic Motion Therapy (DMT) Platform is advocated as a non-drug, non-invasive treatment for osteoporosis.  It provides very small vertical movements of about 50 micrometers that repeat at a rate of approximately 34 times/second.  This repetition rate is automatically varied to correspond to an individual's body mass.  Consequently, the vertical motion transmitted to the musculoskeletal system by the Juvent Platform is barely noticeable.  The user supposedly can obtain the full benefits of the Juvent therapy by standing on the Juvent 1000 Platform for 20 minutes each day.  However, there is a lack of evidence regarding the effectiveness of this device.

MEDEK, a form of physiotherapy, refers to Metodo Dinamico de Estimulacion Kinesica or Dynamic Method for Kinetic Stimulation.  It was developed by a Chilean physical therapist in the 1970s.  MEDEK is used for developing gross motor skills in children with physical disabilities and movement disorders (e.g., cerebral palsy, Down syndrome, hypotonia, muscular dystrophy, and developmental motor delay).  It does not focus on modifying muscle tone, primitive reflexes or abnormal patterns of movement.  It focuses on training movements leading to sitting, standing, and walking.  Muscles are trained in postural and functional tasks rather than in isolation.  Tight muscles are stretched in dynamic situations.  The motor developmental sequence is not used.  MeDEK assumes that different skills require different movement strategies.  Unlike other interventions, tasks are performed without the child’s attention, conscious thought or co-operation.  It is assumed that motivation will increase temporary performance only but will not create a permanent change.  The therapist’s task is to provoke automatic postural reactions that contribute to the postural control needed for functional tasks.  Well-designed clinical studies are needed to ascertain the effectiveness of MEDEK.

In a review on autism, Levy and colleagues (2009) stated that popular biologically based treatments include anti-infectives, chelation medications, gastrointestinal medications, hyperbaric oxygen therapy, and intravenous immunoglobulins.  Non-biologically based treatments include auditoru integration therapy, chiropractic therapy, cranio-sacral manipulation, facilitated communication, interactive metronome, and transcranial stimulation.  However, few studies have addressed the safety and effectiveness of most of these treatments.

According the American Cancer Society, there is no scientific evidence that hydrogen peroxide is a safe, effective or useful cancer treatment.  Current mainstream medical applications of hydrogen peroxide are limited to 1.5 % to 3 % solutions used as surface disinfectants and wound cleansers.

Traumeel injection solution is an anti-inflammatory, anti-edematous, anti-exudative combination formulation of 12 botanical substances and 1 mineral substance.  It is classified as a homeopathic combination remedy.

Botanical Ingredients

• Aconitum napellus (monkshood)
• Arnica montana, radix (mountain arnica)
• Belladonna (deadly nightshade)
• Bellis perennis (daisy)
• Calendula officinalis (marigold)
• Chamomilla (chamomile)
• Echinacea angustifolia (narrow-leafed cone flower)
• Echinacea purpurea (purple cone flower)
• Hamamelis virginiana (witch hazel)
• Hypericum perforatum (St. John's wort)
• Millefolium (milfoil)
• Symphytum officinale (comfrey)

Mineral Ingredient

• Hepar sulphuris calcareum (calcium sulfide)

Ina Cochrane review, Kassab and colleagues (2009) evaluated safety and effectiveness of homeopathic medicines used to prevent or treat adverse effects of cancer treatments.  Randomized controlled trials (RCTs) of homeopathic medicines in participants with a clinical or histological diagnosis of cancer where the intervention was aimed at preventing or treating symptoms associated with cancer treatments were included in this review.  All age groups, and all stages of disease were included.  Two review authors independently assessed studies for inclusion and 2 review authors extracted data.  Three review authors independently assessed trial quality using the Delphi List and the Cochrane Collaboration's tool for assessing risk of bias.  Disagreements were resolved by consensus.  Where available, data were extracted for analysis.  A total of 8 controlled trials (7 placebo controlled and 1 trial against an active treatment) with a total of 664 participants met the inclusion criteria.  Three studied adverse effects of radiotherapy, 3 studied adverse effects of chemotherapy and 2 studied menopausal symptoms associated with breast cancer treatment.  Two studies with low-risk of bias demonstrated benefit: one study with 254 subjects demonstrated superiority of topical calendula over trolamine (a topical agent not containing corticosteroids) for prevention of radiotherapy-induced dermatitis, and another study with 32 subjects demonstrated superiority of Traumeel S (a proprietary complex homeopathic medicine) over placebo as a mouthwash for chemotherapy-induced stomatitis.  Two other studies reported positive results, although the risk of bias was unclear, and 4 further studies reported negative results.  No serious adverse effects or interactions were reported attributable to the homeopathic medicines used.  The authors concluded that this review found preliminary data in support of the efficacy of topical calendula for prophylaxis of acute dermatitis during radiotherapy and Traumeel S mouthwash in the treatment of chemotherapy-induced stomatitis.  Moreover, they stated that these trials need replicating.  There is no convincing evidence for the efficacy of homeopathic medicines for other adverse effects of cancer treatments.  Further research is required.

In a randomized controlled trial, Singer et al (2010) evaluated the effectiveness of the homeopathic preparation Traumeel S in minimizing post-operative pain and analgesic consumption following surgical correction of hallux valgus.  A total of 80 consecutive patients were randomized to receive either Traumeel tablets or an indistinguishable placebo, and took primary and rescue oral analgesics as needed.  Maximum numerical pain scores at rest and consumption of oral analgesics were recorded on day of surgery and for 13 days following surgery.  Traumeel was not found superior to placebo in minimizing pain or analgesic consumption over the 14 days of the trial, however a transient reduction in the daily maximum post-operative pain score favoring the Traumeel arm was observed on the day of surgery, a finding supported by a treatment-time interaction test (p = 0.04).  The authors concluded that Traumeel was not superior to placebo in minimizing pain or analgesic consumption over the 14 days of the trial.  A transient reduction in the daily maximum post-operative pain score on the day of surgery is of questionable clinical importance.

Biomagnetic therapy is an approach to pain-relief that employs the use of magnets to generate an electro-magnetic field (EMF) to areas of musculo-skeletal discomfort or injuries.  This approach can reportedly reduce the discomfort arising from various degenerative diseases (e.g., osteoarthritis) and help in the recovery of joint or tendon injury.  However, the exact mechanism(s) of these recuperative effects remain elusive.  Further ambiguity also stems from the fact that the reported effectiveness of this intervention is based largely on subjective experiences of participants in clinical trials that display a significant investigators' bias as well as placebo-effect.  Thus, the effectiveness of biomagnetic therapy for pain-relief has yet to be established.

Lorentzen et al (2012) stated that neural tension technique (NTT) is a therapy believed to reduce spasticity and to increase range of motion (ROM).  These investigators compared the ability of NTT and random passive movements (RPMs) to reduce spasticity in the knee flexors in 10 spastic patients with brain injury.  An RCT study with cross-over design evaluated muscle tone measured by:

1. hand-held dynamometer;
2. Modified Ashworth Scale (MAS); and ROM by angles of resistance onset "catch" (R1) compensatory movement (R2) and "subjectively perceived reduction in muscle tone". 

Outcome measures were recorded by 3 raters before and after a single treatment session.  Objective stiffness measured with the hand-held device showed no significant changes for the NTT or RPM (p ≥ 0.09 to 0.79).  The subjective measures showed significant changes after the NTT for the non-blinded rater (MAS: p < 0.05: R1: p < 0.05; R2: p < 0.05), but for the blinded rater a significant reduction was found only for R1 (p < 0.05) and R2 (p < 0.05).  For the non-blinded rater, intervention effects were found for R1 (p < 0.01), R2 (p < 0.01) and subjectively perceived tone reduction (p < 0.01).  For the blinded rater, no intervention effect was found.  The authors concluded that an objective evaluation of NTT demonstrated that it does not reduce spasticity.  However, it does increase ROM with the same effect as RPM.

Hivamat therapy (deep oscillation therapy) utilizes an intermittent electrostatic field via a Hivamat machine.  It supposedly penetrates deeper into the body tissue than manual methods, allowing previously “untreatable” injuries to be manipulated with a minimum of physical pressure.  Electrostatic waves create a kneading effect deep within the damaged tissues, restoring flexibility and blood supply to the affected area. 

Aliyev (2009) noted that in Germany approximately 2 million sports injuries occur per year.  Most common are distortions and ligamentous injury going along with post-traumatic lymphedema.  Deep oscillation therapy provided very good results in lymph drainage and in other indications.  In an experimental study, these researchers evaluated the effects of deep oscillation therapy in immediate therapy and after-care of different sports injuries in addition to usual care (complex physical and medical therapy).  Two soccer teams were supported by a sports medicine section of a rehabilitation hospital.  In 14 people (mean age of 23.9 years), 49 sports injuries of different kind were treated.  Subjective rating of the symptoms by visual analog scale (VAS) improved significant (p = 0.001) from 8.7 (baseline) to 2.1 points (post-treatment).  Objective rating by the attending physician according to different clinically relevant parameters lead to "very good" or "good" results in 90 % of the patients.  The authors concluded that deep oscillation therapy is an easy to use and comparably cost-effective adjuvant therapy option.  These investigators already had good experience with it in other indications concerning re-absorption of edema, reducing pain, anti-inflammatory effect, promotion of motoricity, promotion of wound healing, anti-fibrotic effect and improvement in trophicity and quality of the tissue.  All these mentioned effects can be confirmed in the treatment of patients with acute sports injury and trauma.  The soft mode of action is the reason that in contrast to other electric and mechanical therapies it is no contraindication in immediate therapy.  In general, the authors noted no side effects; patients were highly compliant and rated this therapy as very good.  Limitations of this small study (n = 14) were its retrospective and uncontrolled nature; findings were also confounded by the concomitant use of usual care.

The Regenokine therapy appears to be a new therapeutic approach for treating osteoarthritis and low back pain.

There is a lack of reliable evidence to support the use of insulin potentiation therapy.  The American Cancer Society (2008) described insulin potentiation therapy as the use of insulin along with lower doses of chemotherapy to treat cancer.  The American Cancer Society concluded that “Despite supporters' claims that insulin potentiation therapy has been well researched, no scientific studies that show safety and effectiveness have been published in available peer-reviewed journals.  These claims cannot be verified”.

Mora-Ripoll (2011) noted that scientific research has shown that laughter may have both preventive and therapeutic values.  Health-related benefits of laughter are mainly reported from spontaneous laughter interventional studies.  While the human mind can make a distinction between simulated and spontaneous laughter, the human body cannot.  Either way health-related outcomes are deemed to be produced.  Simulated laughter is thus a relatively under-researched treatment modality with potential health benefits.  The aim of this review was firstly to identify, critically evaluate and summarize the laughter literature; secondly to assess to which extent simulated laughter health-related benefits are currently sustained by empirical evidence; and lastly to provide recommendations and future directions for further research.  A comprehensive laughter literature search was performed.  A list of inclusion and exclusion criteria was identified.  Thematic analysis was applied to summarize laughter health-related outcomes, relationships, and general robustness.  Laughter has shown different physiological and psychological benefits.  Adverse effects are very limited and laughter is practically lacking in counter-indications.  Despite the limited number of publications, there is some evidence to suggest that simulated laughter has also some effects on certain aspects of health, though further well-designed research is warranted.  The author concluded that simulated laughter techniques can be easily implemented in traditional clinical settings for health and patient care.  Their effective use for therapeutic purposes needs to be learned, practiced, and developed as any other medical strategy.  They stated that practical guidelines and further research are needed to help health care professionals (and others) implement laughter techniques in their health care portfolio.

Lebowitz et al (2011) stated that little is known about the physical and psychological effects of sense of humor and laughter among patients with chronic obstructive pulmonary disease (COPD).  These investigators examined the effects of humor and laughter on psychological functioning, quality of life, health status, and pulmonary functioning among patients with COPD (n = 46; mean age ± SD, 66.9 ± 9.9 years).  Subjects completed assessments of sense of humor, depression, anxiety, quality of life, and recent illness.  A subset of patients (n = 22) completed a laughter induction study and were randomly assigned to view either a humorous or a neutral video.  Pulmonary function, mood state, and dyspnea were assessed before and after the video.  Sense of humor was associated with fewer symptoms of depression and anxiety and an enhanced quality of life.  However, the induction of laughter led to lung hyper-inflation.  The authors concluded that sense of humor among patients with COPD is associated with positive psychological functioning and enhanced quality of life, but laughing aloud may cause acute deterioration in pulmonary function secondary to worsened hyper-inflation.

Mistletoe (Iscador) is an extract that is used mainly in Europe as a treatment for cancer.  The extract is injected subcutaneously near a tumor to slow and possibly reverse tumor growth.  Ostermann et al (2009) examined the survival of cancer patients treated with mistletoe extract.  These investigators searched several databases such as Cochrane, EMBASE, NCCAM, NLM, DIMDI, CAMbase, and Medline.  Inclusion criteria were controlled clinical studies on parameters associated with survival in cancer patients treated with Iscador.  Outcome data were extracted as they were given in the publication, and expressed as hazard ratios (HR), their logarithm, and the respective standard errors using standard formulas.  These researchers found 49 publications on the clinical effects of Iscador usage on survival of cancer patients that met selection criteria.  Among them, 41 studies and strata provided enough data to extract HR and their standard errors (Iscador versus no extra treatment).  The majority of studies reported positive effects in favor of the Iscador application.  Heterogeneity of study results was moderate (I2 = 38.3 %, p < 0.0001).  The funnel plots were considerably skewed, indicating a publication bias, a notion which is corroborated by statistical means (AC = -1.3, confidence interval [CI]: -1.9 to -0.6, p <= 0.0001).  A random effect meta-analysis estimated the overall HR = 0.59 (CI: 0.53 to 0.66, p < 0.0001).  Randomized studies showed less effects than non-randomized studies (ratio of HRs: 1.24, CI: 0.79 to 1.92, p = 0.35), and matched-pair studies gave significantly better results than others (ratio of HRs: 0.33; CI: 0.17 to 0.65, p = 0.0012).  The authors concluded that pooled analysis of clinical studies suggested that adjuvant treatment of cancer patients with the mistletoe extract Iscador is associated with a better survival.  Despite obvious limitations, and strong hints for a publication bias that limited the evidence found in this meta-analysis, one cannot ignore the fact that studies with positive effects of VA-E on survival of cancer patients are accumulating.  They stated that future studies evaluating the effects of Iscador should focus on a transparent design and description of endpoints in order to provide greater insight into a treatment often being depreciated as ineffective, but highly valued by cancer patients.

Ritter et al (2010) reported the case of a 43-year old woman who was diagnosed with pancreatic adenocarcinoma spreading into the regional lymph nodes and into multiple liver segments (pT3, pN1, pM1).  Upon diagnosis, she underwent a pylorus-preserving pancreatic head resection, including dissection of regional lymph nodes and atypical resection of a single liver segment, followed by 9 cycles of palliative chemotherapy with gemcitabine and oxaliplatin.  At 37 weeks after surgery, the patient demonstrated a sustained partial remission, and the chemotherapy was stopped.  Surprisingly, 10 months later, she still showed no evidence of tumor progression.  Since the time of pancreatic surgery, the patient had taken mistletoe extracts and this adjunctive treatment has been continued until now.  The authors concluded that the cases of sustained long-term remission of metastatic pancreatic cancer are extremely rare.  Although this single case observation does not allow for firm conclusions regarding potential mechanisms, the adjunctive therapy with mistletoe extracts might have played a role.  Thus, they stated that the clinical effects of such treatment in patients with pancreatic cancer warrant further investigation.

Kirsch and Hajto (2011) presented several favorable clinical responses of patients who had sarcoma and who were treated with immunologically effective mistletoe (Viscum album L) extracts (ME) preparations.  In accordance with the bell-shaped dose-response relationship of mistletoe lectins (ML), the patients with sarcoma were treated with ME preparations, standardized for the active sugar-binding lectin contents.  Thus, an optimal dose of 0.75 to 1.0 ng/kg ML was given twice a week subcutaneously.  In this report, the clinical progress of 6 patients with sarcoma showed remissions of tumor symptoms.  The authors concluded that it seems that this disease is beneficially influenced by optimized lectin-oriented ME therapy since patients with sarcoma may react especially well to the improved balance of natural immunological mechanisms.  They stated that these case reports require further clinical studies in patients with sarcoma.

The National Cancer Institute (2012) stated that “At present, the use of mistletoe cannot be recommended outside the context of well-designed clinical trials”.

Muscle testing is often referred to as applied kinesiology, although the two are not the same.  Muscle testing refers to a non-invasive way of evaluating the body’s imbalances and assessing its needs.  It entails testing the body’s responses when applying slight pressure to a large muscle, to provide information on energy blockages, the functioning of the organs, nutritional deficiencies (vitamins and minerals), as well as food sensitivities.  Furthermore, muscle testing can also be used to test the body’s responses to herbs and other remedies.  However, there is a lack of evidence regarding the clinical value of this type of testing, whether electronically or manually. 

In a systematic review with meta-analysis, Lim and colleagues (2011) compared pain and disability in individuals with persistent non-specific low back pain (LBP) who were treated with Pilates exercises compared to minimal or other interventions.  Searches of Medline, CINAHL, Embase, Cochrane library, PEDro, and ProQuest Dissertations and Thesis databases were conducted.  Randomized controlled trials were selected and reviewed if they compared pain and disability in individuals with persistent non-specific LBP who were treated with Pilates exercises compared to other treatment approaches.  Quality of the trials was evaluated.  Data for pain and disability scores were extracted.  Narrative synthesis plus meta-analyses were performed with a fixed-effects or random-effects model, standardized mean differences (SMDs), and tests for heterogeneity.  A total of 7 RCTs were identified and included in the meta-analyses.  Data pooling was performed using RevMan 5.  When compared to minimal intervention, Pilates-based exercise provided superior pain relief (pooled SMD, -2.72; 95 % CI: -5.33 to -0.11; p = 0.04) but the pooled disability scores were not significantly different (pooled SMD, -0.74; 95 % CI: -1.81 to 0.33; p = 0.17).  No significant differences were found when comparing Pilates-based exercise to other forms of exercise for pain (pooled SMD, 0.03; 95 % CI: -0.52 to 0.58; p = 0.92) or disability scores (pooled SMD, -0.41; 95 % CI: -0.96 to 0.14; p = 0.14).  The authors concluded that Pilates-based exercises are superior to minimal intervention for pain relief.  However, existing evidence does not establish superiority of Pilates-based exercise to other forms of exercise to reduce pain and disability for patients with persistent non-specific LBP.  Moreover, the relatively low quality of existing studies and the heterogeneity of pooled studies in this systematic review combine to suggest that these results should be interpreted with caution.

Pereira et al (2012) performed a systematic review with meta-analyses that evaluates the effectiveness of the Pilates method on the pain and functionality outcome in adults with non-specific chronic LBP.  The search was performed in the following databases: Medline, Embase, AMED, Cinahl, Lilacs, Scielo, SportDiscus, ProQuest, Web of Science, PEDro, Academic Search Premier and the Cochrane Central Register of Controlled Trials from 1950 to 2011; the following keywords were used: 'Pilates', 'Pilates-based', 'back exercises', 'exercise therapy', 'low back pain', 'back pain' and 'backache'.  The inclusion criteria were studies that assessed the effects of the Pilates method on patients with chronic LBP.  A total of 5 studies met the inclusion criteria.  The total number of patients was 71 in the Pilates group and 68 in the control group.  Pilates exercise did not improve functionality (standardized mean difference (SMD = -1.34; 95 % CI: -2.80 to 0.11; p = 0.07) or pain between Pilates and control groups (SMD = -1.99; 95 % CI: -4.35 to 0.37; p = 0.10).  Pilates and lumbar stabilization exercises presented no significant difference in functionality (mean difference (MD) = -0.31; 95 % CI: -1.02 to 0.40; p = 0.39) or pain (MD = -0.31; 95 % CI: -1.02 to 0.40; p = 0.39).  The authors concluded that Pilates method did not improve functionality and pain in patients who have LBP when compared with control and lumbar stabilization exercise groups.

Thermogenic therapy refers to the production of artificial fever; it has been in use since 1919 in the treatment of certain types of resistant infectious diseases, rheumatoid arthritis and Sydenham's chorea.  There is a lack of evidence regarding the effectiveness of this therapy.

Wesselius et al (2005) noted that bee sting therapy is increasingly used to treat patients with multiple sclerosis (MS) in the belief that it can stabilize or ameliorate the disease.  However, there are no clinical studies to justify its use.  In a randomized, cross-over study, these investigators assigned 26 patients with relapsing-remitting or relapsing secondary progressive MS to 24 weeks of medically supervised bee sting therapy or 24 weeks of no treatment.  Live bees (up to a maximum of 20) were used to administer bee venom 3 times per week.  The primary outcome was the cumulative number of new gadolinium-enhancing lesions on T1-weighted MRI of the brain.  Secondary outcomes were lesion load on T2^*-weighted MRI, relapse rate, disability (Expanded Disability Status Scale, Multiple Sclerosis Functional Composite, Guy's Neurologic Disability Scale), fatigue (Abbreviated Fatigue Questionnaire, Fatigue Impact Scale), and health-related quality of life (Medical Outcomes Study 36-Item Short Form General Health Survey).  During bee sting therapy, there was no significant reduction in the cumulative number of new gadolinium-enhancing lesions.  The T2^*-weighted lesion load further progressed, and there was no significant reduction in relapse rate.  There was no improvement of disability, fatigue, and quality of life.  Bee sting therapy was well-tolerated, and there were no serious adverse events.  The authors concluded that in this trial, treatment with bee venom in patients with relapsing MS did not reduce disease activity, disability, or fatigue and did not improve quality of life.

Also, the American Academy of Neurology’s evidence-based guideline on “Complementary and alternative medicine in multiple sclerosis” (Yadav et al, 2014) stated that bee sting therapy is possibly ineffective for relapses and Cari Loder regimen (lofepramine plus phenylalanine with B12) is possibly ineffective for disability, symptoms, depression, and fatigue.

Ali and colleagues (2009) stated that intravenous micronutrient therapy (IVMT), and specifically the Myers' Cocktail, is a popular approach for treating fibromyalgia syndrome (FMS) among complementary and alternative medicine practitioners, but its effectiveness is uncertain.  In a randomized, double-blind, placebo-controlled pilot study, these researchers evaluated the feasibility, safety, and provided insights into the effectiveness of this therapy.  Subjects were 34 adults with American College of Rheumatology (ACR)-defined FMS.  They were randomly assigned either to treatment (weekly infusions of IVMT) or to placebo (weekly infusions of lactated Ringer's solution) for 8 weeks.  Primary outcome was change in the Tender Point Index, assessed 8 and 12 weeks after initiation.  Secondary measures included a VAS to assess global pain, and validated measures of physical function (Fibromyalgia Impact Questionnaire), mood (Beck Depression Index), and quality of life (Health Status Questionnaire 2.0).  Clinically significant improvements were noted (of a magnitude similar to other effective interventions).  However, in part because of the high placebo response and the small sample size, no statistically significant differences were seen between groups, in any outcome measure, at 8 and 16 weeks.  Statistically significant within-group differences were seen in both the intervention and placebo groups, demonstrating a treatment effect for both IVMT and placebo.  At 8 weeks, the IVMT group experienced significantly improved tender points, pain, depression, and quality of life directly following treatment (all p < or = 0.02), while the placebo group experienced significantly improved tender points only (p < or = 0.05).  The treatment effects of IVMT persisted at 4 weeks post-intervention for tender points, pain, and quality of life, while placebo effects persisted only for tender points.  A single minor adverse event was noted in 1 subject in the intervention group.  The authors conclude that this pilot study established the safety and feasibility of treating FMS with IVMT.  Most subjects experienced relief as compared to baseline, but no statistically significant differences were seen between IVMT and placebo.  They stated that the effectiveness of IVMT for fibromyalgia, relative to placebo, is as yet uncertain.

Schencking et al (2012) noted that vitamin C (ascorbic acid) is an immune-relevant micronutrient, which is depleted in viral infections and this deficiency seems to play a critical role in the pathogenesis of herpes infections and in the development of post-herpetic neuralgia (PHN).  In an observational multi-center study, these researchers evaluated the utilization, safety and effectiveness of intravenously administrated vitamin C in patients with shingles.  Between April 2009 and December 2010, a total of 16 general practitioners recorded data of 67 participants with symptomatic herpes zoster who received vitamin C intravenously (Pascorbin^® 7.5 g/50 ml) for approximately 2 weeks in addition to standard treatment.  The assessment of pain (VAS) and the dermatologic symptoms of shingles such as hemorrhagic lesions and the number of efflorescences were investigated in a follow-up observation phase of up to 12 weeks.  Mean declines of pain scores (VAS), number of affected dermatomes and efflorescences, and the presence of hemorrhagic vesicles between the baseline and follow-up assessments at 2 and 12 weeks were statistically significant.  Overall, 6.4 % of the participants experienced PHN.  Common complaints such as general fatigue and impaired concentration also improved during the study.  The effects and the tolerability of the treatment were evaluated positively by the physicians.  The risk of developing PHN was reduced.  The authors concluded that these findings provided evidence that concomitant use of intravenously administered vitamin C may have beneficial effects on herpes zoster-associated pain, dermatologic findings and accompanying common complaints.  Moreover, they stated that randomized, placebo-controlled clinical studies are needed to confirm these findings.

Buteyko Breathing Technique

In a Cochrane review on “Breathing exercises for adults with asthma”, Freitas et al (2013) concluded that “even though individual trials reported positive effects of breathing exercises, no reliable conclusions could be drawn concerning the use of breathing exercises for asthma in clinical practice.  This was a result of methodological differences among the included studies and poor reporting of methodological aspects in most of the included studies.  However, trends for improvement are encouraging, and further studies including full descriptions of treatment methods and outcome measurements are required”.

Furthermore, an UpToDate review on “Complementary, alternative, and integrative therapies for asthma” (Martin, 2016) states that “Behavioral therapies -- Data are conflicting about the benefit of biofeedback, functional relaxation, and breathing exercises for patients with asthma, although some patients appear to derive benefit …. Breathing techniques designed to prolong exhalation and decrease minute ventilation have been studied as non-pharmacologic therapies for asthma.  Pranayama, or yoga breathing exercises, emphasize deep respiration with slow exhalation.  Similarly, Buteyko breathing exercises were developed based on the theory that a reduction in minute ventilation might improve asthmatic control.  Most studies of these approaches show no significant benefit, but have been limited by small sample size or retrospective analysis.  However, data from systematic reviews and randomized controlled trials provide evidence of benefit, although confirmation is needed with additional trials that better specify baseline breathing patterns and are free of methodologic concerns”.

Glutathione Infusion

Exner et al (2000) stated that reactive oxygen species (ROS), formed in various biochemical reactions, are normally scavenged by antioxidants.  Glutathione in its reduced form (GSH) is the most powerful intracellular anti-oxidant, and the ratio of reduced to oxidized glutathione (GSH:GSSG) serves as a representative marker of the anti-oxidative capacity of the cell.  Several clinical conditions are associated with reduced GSH levels which as a consequence can result in a lowered cellular redox potential.  GSH and the redox potential of the cell are components of the cell signaling system influencing the translocation of the transcription factor NF kappa B which regulates the synthesis of cytokines and adhesion molecules.  Therefore, one possibility to protect cells from damage caused by ROS is to restore the intracellular glutathione levels.  Cellular GSH concentration can be influenced by exogenous administration of GSH (as intravenous infusion or as aerosol), of glutathione esters or of GSH precursors such as glutamine or cysteine (in form of N-acetyl-L-cysteine, alpha-lipoic acid).  The modulation of GSH metabolism might present a useful adjuvant therapy in many pathologies such as intoxication, diabetes, uremia, sepsis, inflammatory lung processes, coronary disease, cancer and immunodeficiency states. 

Logan and Wong (2001) noted that chronic fatigue syndrome (CFS) is an illness characterized by persistent and relapsing fatigue, often accompanied by numerous symptoms involving various body systems.  The etiology of CFS remains unclear; however, a number of recent studies have shown oxidative stress may be involved in its pathogenesis.  The role of oxidative stress in CFS is an important area for current and future research as it suggests the use of anti-oxidants in the management of CFS.  Specifically, the dietary supplements glutathione, N-acetylcysteine, alpha-lipoic acid, oligomeric proanthocyanidins, ginkgo biloba, and vaccinium myrtillus (bilberry) may be beneficial.  In addition, research on food intolerance was discussed, since food intolerance may be involved in CFS symptom presentation and in oxidation via cytokine induction.

Cersosimo (2005) reviewed the incidence, mechanism, signs, symptoms, and management of oxaliplatin-induced neurotoxicity.  Data sources included English-language publications from the MEDLINE database (1995 to August 2004), published articles, and meeting abstracts were reviewed.  Relevant data were extracted from published reports and abstracts on studies and case reports of humans with cancer who received oxaliplatin chemotherapy and in-vitro studies of oxaliplatin neurotoxicity.  Neurotoxicity is a common adverse effect of oxaliplatin that usually presents as peripheral neuropathy.  There are 2 forms of oxaliplatin-induced neurotoxicity:

1. acute and
2. chronic.

The acute form occurs in greater than 90 % of patients and may begin during the infusion or within hours of completion, is usually self-limited, and may be exacerbated by exposure to cold.  Chronic neuropathy is cumulative and is most commonly seen in patients who have received total doses greater than or equal to 540 mg/m2.  Although it is a sensory neuropathy, the intensity can increase to the point that it impairs physical functions, such as holding objects and writing.  Preventive measures include administration of calcium and magnesium solutions, gabapentin, carbamazepine, amifostine, and glutathione.  Treatment measures include calcium and magnesium solutions, gabapentin, and alpha-lipoic acid.  The authors concluded that peripheral neuropathy is seen in the majority of patients who receive oxaliplatin.  The acute form is usually transient and self-limited; however, the chronic form can be dose-limiting.  Calcium and magnesium solutions are an effective and convenient means of treating and reducing the severity of neuropathic symptoms.  Moreover, they stated that additional studies, including controlled trials, are needed to determine the best way to prevent and treat this complication.

Nazıroglu et al (2013) noted that contrast media (CM)-induced nephropathy is a common cause of iatrogenic acute renal failure.  These investigators discussed the mechanisms and risk factors of CM, summarized the controlled studies evaluating measures for prevention and concluded with evidence-based strategies for prevention.  They reviewed the relevant literature and results from recent clinical studies as well as critical analyses of published systematic reviews used MEDLINE and the Science Citation Index.  The cytotoxicity induced by CM leads to apoptosis and death of endothelial and tubular cells and may be initiated by cell membrane damage together with ROS and inflammation.  Cell damage may be aggravated by factors such as tissue hypoxia, properties of individual CM such as ionic strength, high osmolarity and/or viscosity.  The authors stated that clinical studies indeed support this possibility, suggesting a protective effect of ROS scavenging with the administration of N-acetylcysteine, ascorbic acid erdosteine, glutathione and bicarbonate infusion.

The Academy of Nutrition and Dietetics’ practice guideline on “Oncology evidence-based nutrition” (2013) stated that “If an adult oncology patient is at risk for or has chemotherapy-induced peripheral neuropathy (CIPN), the RDN should advise the patient that the use of nutrition substances (vitamin E, calcium and magnesium infusions, acetyl-L-carnitine, glutamine, glutathione) may or may not be beneficial as a means of preventing or improving CIPN.  Research indicates that these substances have had only limited success in preventing or improving CIPN in oncology patients receiving specific chemotherapeutic agents”.

Salt Room Therapy

Hedman et al (2006) stated that randomized controlled trials are needed to evaluate the effects of complementary treatments in asthma.  This study assessed the effect of salt chamber treatment as an add-on therapy to low-to-moderate inhaled steroid therapy in asthma patients with bronchial hyper-responsiveness (BHR).  After a 2-week baseline period, 32 asthma patients who exhibited BHR in the histamine inhalation challenge were randomized: 17 to 2-week active treatment, during which salt was fed to the room by a salt generator, and 15 to placebo.  The salt chamber treatment lasted 40 minutes and was administered 5 times a week.  Median provocative dose causing a decrease of 15 % in Fev(1) (PD(15)FEV(1)) [corrected] increased significantly in the active group (p = 0.047) but not in the placebo group.  The difference in changes between the active and placebo groups was significant (p = 0.02); 9 patients (56 %) in the active group and 2 patients (17%) in the placebo group exhibited at least 1 doubling dose decrease in BHR (p = 0.040); 6 patients (38 %) in the active group and none in the placebo group became non-hyperresponsive (p = 0.017).  Neither the peak expiratory flow (PEF) values measured just before and after the treatment, nor FEV(1) values measured before the histamine challenges, changed.  The reduction in BHR was not caused by changes in the baseline lung function.  The authors concluded that salt chamber treatment reduced bronchial hyper-responsiveness as an add-on therapy in asthmatics with a low-to-moderate dose of inhaled steroids.  They stated that the possibility that salt chamber treatment could serve as a complementary therapy to conventional medication cannot be excluded.

While this was a randomized study, the sample size was (n = 17 received salt chamber treatment) and its findings were confounded by the combinational use of inhaled steroids.  Moreover, these findings do not appear to have been duplicated.

Vibro-Acoustic Therapy

Lukasiak et al (2013) stated that the so-called "heel spur" is a radiological term referring to adaptive bone growth as a result of chronic over-load enthesopathy of the proximal attachment of the plantar fascia.  The main cause of the pain is continued localized pressure on the surrounding soft tissues.  Vibro-acoustic wave therapy is a relatively new method gaining popularity among doctors, physiotherapists and patients.  These researchers examined the effectiveness of vibro-acoustic therapy compared to laser and ultrasound therapy.  The study enrolled 60 patients treated for plantar heel spurs who were divided into a study group of 40 patients who underwent vibro-acoustic therapy and a control group of 20 patients treated with ultrasound and laser therapy.  The outcome measure for evaluating the effectiveness of physiotherapy was a subjective assessment of pain intensity by VAS and the modified short-form McGill Pain Questionnaire.  The mean pain intensity score in patients undergoing vibro-acoustic therapy decreased by about 2.6 points according to the VAS scale and 17 points according to the McGill questionnaire, compared to reductions of 0.6 and 6 points, respectively, in the ultrasound and laser therapy group.  The correlation between subjective assessment of pain according to the VAS scale and palpation-based assessment of pain was significantly positive between the 2 groups, demonstrating similarity of the 2 scales, with a slight dominance of the group undergoing laser and ultrasound therapy.  The authors concluded that these findings represented a tentative confirmation of analgesic effectiveness of the vibro-acoustic method in musculoskeletal over-load conditions.  They stated that in order to confirm its effectiveness, it is necessary to conduct further prospective randomized studies with blinding and evaluate the long-term results.

Musgutova Neurosensorimotor Reflex Integration (MNRI) Method

The Masgutova Method is a set of programs focused on the restoration and maturation of primary movements, reflexes, coordination systems, skills for optimal performance of natural mechanisms, developmental processes, brain functioning, and sensory-motor integration. The Masgutova Method is oriented on the stimulation of reflex patterns in order to awaken natural, genetic motor resources, self-regenerating strength of motor memory and sensory-motor coherence.  This achievement innately carries the implication of the fulfillment of all potentials within movement abilities and learning skills.

Pilecki et al (2012) stated that rehabilitation therapy in children with neuromotor development disorders can be carried out with the use of various methods. These researchers determined the efficiency of rehabilitation carried out with the use of the new therapeutic method MNRI (Masgutova Neurosensorimotor Reflex Integration) in children with cerebral palsy (CP) by objective measurements with a brainstem auditory evoked potentials (BAEP) examination.  Besides the known parameters, Inter-peak Latency I-V (IPL I-V) in BAEP, an original parameter proposed by Pilecki was introduced, called a relative IPL I-V value.  The study involved a group of 17 children (9 girls and 8 boys) aged from 1.3 to 5.9 years (mean of 3.8, SD = 1.3) with CP.  Due to difficulty in co-operation, analysis of only 15 children could be finished.  Analysis of the absolute IPL I-V values showed that after rehabilitation the percentage of the results with slowed transmission, i.e., those in which the IPL I-V value was prolonged, decreased from more than 88 % to 60 %.  The assessment of the relative IPL I-V values showed that the results obtained after rehabilitation are more advantageous.  The authors concluded that as a result of rehabilitation carried out by the MNRI method in children with CP, a significant improvement in the transmission in the brainstem section of the auditory pathway was observed based on the absolute and relative IPL I-V values.  However, the change obtained in children was various.

Wilderness Programs

Shanahan et al (2009) highlighted the potential application of Wilderness Adventure Therapy (WAT) as a supplementary tool in cognitive rehabilitation with an adolescent traumatic brain injury (TBI) population. A review of existing literature pertaining to adolescent TBI, cognitive rehabilitation approaches and WAT was conducted.  Literature was sourced through EBSCOhost (Health and Psychology), Informaworld, Informit Online and Ovid.  Key search terms used were: adolescent, adventure therapy, at-risk, brain injury, cognitive rehabilitation, delinquent, head injury, pediatric, outdoor education, wilderness adventure therapy and youth.  Three articles that discussed the use of WAT with adult TBI cohorts were identified; no research reporting the use of WAT with an adolescent TBI cohort was located.  The review highlighted theoretical and practice similarities between cognitive rehabilitation and WAT, with both proving to be examples of “contextualized intervention”.  The majority of WAT literature reported programs aimed at at-risk and delinquent youth and, again, similarities in the difficulties experienced by these adolescents and adolescents with TBI were apparent.  The authors concluded that a trial that examines the application of WAT with adolescents with TBI is needed.  Outcomes for executive functioning skill development, self-esteem development and quality-of-life post-program should be ascertained to compare with results from adult programs.

Mutz and Muller (2016) examined potential mental health benefits of outdoor and adventure education programs. It is argued that experiences made in successful programs can increase self-efficacy, mindfulness and subjective well-being.  Furthermore, programs may reduce feelings of time pressure and mental stress amongst participants.  Evidence comes from 2 pilot studies: In the school project "Crossing the Alps" (Study 1), 14-year old participants reported an increase in life satisfaction, mindfulness and a decrease in the Pediatric Sleep Questionnaire (PSQ) Subscale “demand” after a successful 9-day hike through the German, Austrian, and Italian Alps.  In the university project "Friluftsliv" (Study 2) participants scored higher in life satisfaction, happiness, mindfulness, and self-efficacy and lower in perceived stress after having spent 8 days in the wilderness of the Norwegian Hardangervidda region, miles away from the next locality.  The authors concluded that the findings suggested that outdoor education and wilderness programs can foster mental health in youths and young adults.

Jong et al (2019) stated that long-term childhood cancer survivors are at risk for frailty and have significant health-related issues in adulthood.  Various health promotion interventions have been proposed to enhance QOL including wilderness therapy, which applies the impact of nature on health in a therapeutic context.  Previous studies had described positive outcomes linked with various wilderness-related therapies for cancer survivors.  However, there is no clarity on the role these therapies play in childhood cancer.  The current scoping review aims to systematically map the concept, content and outcome of wilderness therapy for childhood cancer survivors.  This review will be guided by the Joanna Briggs Institute Reviewers' manual for scoping reviews.  A systematic literature search using medical subject headings (MeSH) and text words related to wilderness therapy and childhood cancer survivors will be performed in Embase, ERIC, Medline, Psycinfo, CINAHL, Scopus, Web of Science, SPORTDiscus and Svemed+, Sociological Abstracts, supplemented by grey literature searches.  Eligible quantitative and qualitative studies will be screened, included, assessed for quality and extracted for data by 2 reviewers independently.  Results will be described in a narrative style, reported in extraction tables and diagrams, and where appropriate in themes and text.  The authors concluded that this study described a protocol for a scoping review that will undertake secondary analysis of data already published in literature and is therefore exempt from medical ethical review.  The scoping review will inform understanding of the benefits and risks of wilderness therapy for childhood cancer survivors, their families, practitioners, clinicians and researchers, and will help elucidate the steps necessary for building its evidence base going forward.  Results will be published in a peer-reviewed scientific journal.  One limitation of this proposed study is that no meta-analysis or other statistical analysis will be performed in this review.

Gabrielsen et al (2019) stated that participant state anxiety in outdoor therapeutic practices continues to raise many questions.  These investigators discussed the results of an exploratory pilot study on participant day-to-day state anxiety throughout a Norwegian wilderness therapy intervention.  A total of 33 adolescents from 6 groups completed a total of 251 state sections of the State-Trait Anxiety Inventory.  On average, there was a slight decrease in state anxiety as the program progressed and a significant reduction in anxiety between the first and final days.  The between-subject range was large, and boys reported significantly lower anxiety than did girls.  The authors concluded that in light of the results, they discussed general understandings of day-to-day state anxiety, gender differences, group differences, the perception of risk, and the relationship between perceived autonomy and state anxiety.

Johnson et al (2020) noted that wilderness therapy (WT) is a complementary/integrative approach for treating struggling adolescents by using outdoor adventure activities to foster personal and inter-personal growth/well-being.  Empirical support for the effectiveness of traditional WT is growing, but evidence supporting trauma-informed WT (TIWT) is lacking.  In a pilot study, these researchers addressed that gap.  Between 2009 and 2019, a total of 816 adolescents (ages of 13 to 17 year, mean age = 15.36, SD = 1.25; 41.1 % female) completed the Youth-Outcome Questionnaire-SR 2.0 at intake and discharge (M = 75.02 days, SD = 28.77); 378 adolescents also completed the Family Assessment Device-General Functioning (FAD-GF), and 253 adolescents completed two, 2.5-min segments of heart-rate-variability biofeedback (one while resting and one while using a coping skill); 189 caregivers completed the Youth-Outcome Questionnaire 2.01, and 181 caregivers completed the FAD-GF.  Between 25 and 99 adolescents and caregivers also completed psychological and family measures at 6 months and 1 year post-discharge.  Adolescents reported experiencing improvements in psychological and family functioning.  They also exhibited improvement in psychophysiological functioning (heart-rhythm coherence).  Caregivers reported improvements in family functioning and their child's psychological functioning.  Caregivers observed more persisting benefits in their child's psychological functioning, whereas adolescents reported more persisting benefits in family functioning.  Changes in psychological and family functioning were related.  There were very few differential effects on the basis of demographic factors, trauma exposure, or past and current treatment factors.  The authors concluded that findings of pilot study suggested TIWT is a promising complementary/integrative intervention for improving the psychological, family, and psychophysiological functioning of struggling adolescents.

Furthermore, an UpToDate review on “Psychosocial interventions for substance use disorder in adolescents” (Bukstein, 2021) states that “Longer-term treatment for adolescents with SUD in residential programs, therapeutic communities, and wilderness/adventure programs such as Outward Bound may be available for some adolescents with SUD who have failed less intensive treatment.  There are no randomized clinical trials of the efficacy of these interventions in adolescents.  Observational study of substance use before and after these programs (more extensive for therapeutic communities) provides limited support for them.  Some experts have questioned whether some wilderness/adventure programs might be not only ineffective but potentially harmful to youth, who may be essentially incarcerated and cut off from contact with anyone”.

Vibratory Pads (Vibratory Stimulation)

American Academy of Neurology’s practice guideline summary on “Treatment of restless legs syndrome in adults” (Winkelman et al, 2016) stated that “Vibratory pads (vibratory stimulation) are possibly ineffective in treating RLS symptoms”.

Colon Hydrotherapy

Acosta and Cash (2009) stated that the practice of colonic cleansing to promote general health and well-being continues to generate interest among the lay population.  These practices are widely touted as adjuncts to improve vitality and as therapeutic modalities to minimize the symptoms, or prevent the actual development, of a variety of chronic disease states.  The data supporting colonic cleansing and body "detoxification" have not been studied well in a systematic manner.  This report described a systematic review of the published literature of both the traditional and complementary and alternative medicine arenas that was carried out in an attempt to qualify and quantify the value of colonic cleansing.  The authors concluded that there were no methodologically rigorous controlled trials of colonic cleansing to support the practice for general health promotion.  Conversely, there were multiple case reports and case series that described the adverse effects of colonic cleansing.  They stated that the practice of colonic cleansing to improve or promote general health is not supported in the published literature and cannot be recommended at this time.

Bazzocchi and Giuberti (2017) stated that rigorous studies must be performed on the short- and long-term effectiveness of colonic hydrotherapy.

Gua Sha (Scraping Therapy)

Yuan et al (2015) stated that neck pain (NP) and low back pain (LBP) are common symptoms bothering people in daily life.  Traditional Chinese medicine (TCM) has been used to treat various symptoms and diseases in China and has been demonstrated to be effective.  These researchers reviewed and analyzed the existing data about pain and disability in TCM treatments for NP and LBP.  Studies were identified by a comprehensive search of databases, such as Medline, Embase, and Cochrane Library, up to September 1, 2013.  A meta-analysis was performed to evaluate the efficacy and safety of TCM in managing NP and LBP.  A total of 75 randomized controlled trials (RCTs; n = 11,077) were included.  Almost all of the studies investigated individuals experiencing chronic NP (CNP) or chronic LBP (CLBP).  These researchers found moderate evidence that acupuncture was more effective than sham-acupuncture in reducing pain immediately post-treatment for CNP (visual analogue scale (VAS) 10 cm, mean difference (MD) = -0.58 (-0.94, -0.22), 95 % confidence interval (CI), p = 0.01), CLBP (standardized mean difference = -0.47 (-0.77, -0.17), p = 0.003), and acute LBP (VAS 10 cm, MD = -0.99 (-1.24, -0.73), p < 0.001).  Cupping could be more effective than waitlist in VAS (100 mm) (MD = -19.10 (-27.61, -10.58), p < 0. 001) for CNP or medications (e.g., NSAID) for CLBP (MD = -5.4 (-8.9, -0.19), p = 0.003).  No serious or life-threatening adverse effects were found.  The authors concluded that acupuncture, acupressure, and cupping could be efficacious in treating the pain and disability associated with CNP or CLBP in the immediate term.  Gua sha, tai chi, qigong, and Chinese manipulation showed fair effects, but the authors were unable to draw any definite conclusions, and further research is still needed.  The efficacy of tuina and moxibustion is unknown because no direct evidence was obtained.  These TCM modalities are relatively safe.

Mangesi and Zakarija-Grkovic (2016) presented an update of a systematic review first published by Snowden et al. in 2001 and subsequently published in 2010.  The objective of this update was to seek new information on the best forms of treatment for breast engorgement in lactating women.  These researchers identified studies for inclusion through the Cochrane Pregnancy and Childbirth Group's Trials Register (June 30,  2015) and searched reference lists of retrieved studies.  Two review authors independently assessed trials for eligibility, extracted data and conducted “Risk of bias” assessments.  Where insufficient data were presented in trial reports, these investigators attempted to contact study authors and obtain necessary information. We assessed the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.  The authors concluded that although some interventions such as hot/cold packs, Gua-Sha (scraping therapy), acupuncture, cabbage leaves and proteolytic enzymes may be promising for the treatment of breast engorgement during lactation, there is insufficient evidence from published trials on any intervention to justify widespread implementation.  They stated that more robust research is urgently needed on the treatment of breast engorgement.

In a prospective, randomized, controlled clinical trial, Meng et al (2017) evaluated the effectiveness and safety of Gua sha therapy on peri-menopausal symptoms, quality of life, and serum female hormones in participants with peri-menopausal syndrome.  A total of 80 women with peri-menopausal syndrome were recruited and randomized into an intervention group or a control group.  Participants in the intervention group received 15-minute Gua sha treatment sessions once-weekly plus conventional treatment for 8 weeks, whereas participants in the control group received conventional treatment alone.  The primary outcome was the change in peri-menopausal symptoms and quality of life as obtained through the modified Kupperman Index (KI) and the Menopause-Specific Quality of Life.  The secondary outcome was the change of serum female hormones including estrogen, follicle-stimulating hormone, and luteinizing hormone; 75 out of 80 participants (93.8 %) completed the study -- 38 in the intervention group and 37 in the control group.  The baseline levels of demographic and outcome measurements were comparable between the 2 groups.  After 8 sessions of intervention, the reduction in the total modified KI score was, however, 16.32  ±  4.38 in the intervention group and 11.46  ±  5.96 in the control group, with a difference of 4.86  ±  6.15 (p < 0.01) between the 2 groups.  Also the reductions of hot flash/sweating, paresthesia, insomnia, nervousness, melancholia, fatigue, and headache were greater in the intervention group than in the control group (p < 0.05).  The reduction in the total Menopause-Specific Quality of Life score was 17.87  ±  3.84 in the intervention group and 13.62  ±  7.40 in the control group, with a difference of 4.46  ±  7.52 (p < 0.01) between the 2 groups.  And the scores for vasomotor, psychosocial, and physical domains in the intervention group were significantly lower than those in the control group (p < 0.05).  There were no significant differences in serum estrogen, follicle-stimulating hormone, and luteinizing hormone between the 2 groups.  The authors concluded that the results of this study suggested that Gua sha therapy was effective and safe in relieving peri-menopausal symptoms and improving the quality of life in participants with peri-menopausal syndrome.  The therapy may serve as a promising, effective, non-drug treatment for peri-menopausal syndrome in clinical work.  They stated that additional research is needed to better understand its effectiveness and examine its mechanism for treating peri-menopausal syndrome.

In a pilot, randomized cross-over study, Yuen et al (2017) examined the safety and effectiveness of hydrocollator-based hot pack therapy for the treatment of chronic low back pain.  Pain intensity, physical disability, depression, general health status, and salivary biomarkers were assessed as outcome measures.  Despite there was no significant difference observed between any outcome measures attained by the 2 interventions, several important differences were noted during the 1-week follow-up period.  The magnitudes of pain reduction (21 to 25 % versus 16 to 18 %) and disability improvement (45 to 52 % versus 39 to 42 %) were greater in the Gua sha-treated group than the hot pack group.  Both treatments were shown to improve flexion, extension and bending movements of the lower back, whereas areas of improvement varied between the 2 interventions.  Decreasing trends were observed in both tumor necrosis factor-alpha (TNF-α) and heme-oxygenase-1 (HO-1) levels following Gua sha.  However, rebounds of the biomarkers were observed 1 week following hot pack.  Furthermore, in response to Gua sha, the decrease of TNF-α was strongly correlated with the improvement of physical disability, whereas the physical disability was correlated with the VAS pain intensity.  The authors concluded that this study demonstrated a feasible clinical trial protocol for evaluating the effectiveness of Gua sha and other therapeutic modalities.  Gua sha may exhibit a more long-lasting anti-inflammatory effect relative to hot pack for pain relief and improved mobility in elderly patients with chronic low back pain.

Furthermore, an UpToDate review on “Common problems of breastfeeding and weaning” (Spencer, 2018) states that “Evidence for other supportive measures is limited because engorgement usually resolves over time; therefore, it is difficult to see the effect of specific interventions.  In addition, studies of these measures have included only small numbers of patients and were poorly controlled.  This was best illustrated in a systematic review that found possible benefits of interventions including hot/cold packs, Gua-Sha (scraping therapy), protease complex (plant enzyme), acupuncture, cabbage leaf application, but insufficient evidence to justify widespread use.  Results from the 2 studies using acupuncture showed improved symptoms in the days following treatment, but there was no difference in outcome by six days after treatment.  In the single study using cold gel packs, there appeared to be improvement in symptoms, but differences between the control and intervention groups made it difficult to interpret the results”.

Placentophagy / Placenta Capsules

Young and colleagues (2016) stated that maternal placentophagy has recently emerged as a rare but increasingly popular practice among women in industrialized countries who often ingest the placenta as a processed, encapsulated supplement, seeking its many purported post-partum health benefits.  Little scientific research, however, has evaluated these claims, and concentrations of trace micronutrients/elements in encapsulated placenta have never been examined.  Because the placenta retains beneficial micronutrients and potentially harmful toxic elements at parturition, these researchers hypothesized that dehydrated placenta would contain detectable concentrations of these elements.  To address this hypothesis, they analyzed 28 placental samples processed for encapsulation to evaluate the concentration of 14 trace minerals/elements using inductively coupled plasma mass spectrometry.  Analysis revealed detectable concentrations of arsenic, cadmium, cobalt, copper, iron, lead, manganese, mercury, molybdenum, rubidium, selenium, strontium, uranium, and zinc.  Based on one recommended daily intake of placenta capsules (3,300 mg/day), a daily dose of placenta supplements contains approximately 0.018 ± 0.004 mg copper, 2.19 ± 0.533 mg iron, 0.005 ± 0.000 mg selenium, and 0.180 ± 0.018 mg zinc.  Based on the recommended dietary allowance (RDA) for lactating women, the recommended daily intake of placenta capsules would provide, on average, 24 % RDA for iron, 7.1 % RDA for selenium, 1.5 % RDA for zinc, and 1.4 % RDA for copper.  The mean concentrations of potentially harmful elements (arsenic, cadmium, lead, mercury, uranium) were well below established toxicity thresholds.  The authors concluded that these results indicated that the recommended daily intake of encapsulated placenta may provide only a modest source of some trace micronutrients and a minimal source of toxic elements. 

In a randomized, double-blind, placebo-controlled, pilot study, Gryder and associates (2017) compared the effect of ingested encapsulated placenta on maternal post-partum iron status versus that of a beef placebo.  This trial (n = 23) was conducted among healthy human research participants experiencing a normal pregnancy.  Maternal iron status was measured via hemoglobin, transferrin, and ferritin taken from blood samples drawn in the participants' homes at 4 time-points: the 36th week of pregnancy, within 96 hours of parturition, between days 5 and 7 post-partum, and during week 3 post-partum.  Iron concentrations in the encapsulated placenta and encapsulated beef placebo were compared using inductively coupled plasma mass spectrometry; 78 %  (18/23) of study participants' hemoglobin concentrations were above the World Health Organization (WHO)cut-off for gestational iron deficiency (greater than or equal to 11.0 g/dL) during the 36th week of pregnancy.  Results revealed no statistically significant differences (hemoglobin, p = 0.603; ferritin, p = 0.852; transferrin, p = 0.936) in maternal iron status (including post-partum iron rebound in the 1st week post-partum) between women in the placenta supplement (n = 10) and placebo (n = 13) groups.  Average iron concentrations were considerably higher in encapsulated placenta (0.664 mg/g) compared to the encapsulated beef placebo (0.093 mg/g) but provided only 24 % of the RDA for iron among lactating women based on the study's maximum daily intake.  The authors concluded that the findings of this study suggested that encapsulated placenta supplementation neither significantly improved nor impaired post-partum maternal iron status for women consuming the RDA of dietary iron during pregnancy and lactation, compared to a beef placebo.  This may be an especially important finding for women who are iron deficient post-partum and whose only source of supplemental dietary iron is encapsulated placenta, as this may provide an inadequate source of supplemental iron in cases of deficiency.

In a pilot study, Young et al (2018a) examined if salivary hormone concentrations of women ingesting their own encapsulated placenta during the early post-partum differed from those of women consuming a placebo.  Randomly assigned participants (n = 27) were given a supplement containing either their dehydrated and homogenized placenta (n = 12), or placebo (n = 15).  Saliva samples were collected during late pregnancy and early post-partum.  Samples of participants' processed placenta, and the encapsulated placebo, were also collected.  Hormone analyses were conducted on all samples utilizing liquid chromatography-tandem mass spectrometry.  There were no significant differences in salivary hormone concentrations between the placenta and placebo groups post-supplementation that did not exist pre-supplementation.  There were, however, significant dose-response relationships between the concentration of all 15 detected hormones in the placenta capsules and corresponding salivary hormone measures in placenta group participants not seen in the placebo group.  The higher salivary concentrations of these hormones in the placenta group reflected the higher concentrations of these hormones in the placenta supplements, compared to the placebo.  The authors concluded that some hormones in encapsulated placenta led to small but significant differences in hormonal profiles of women taking placenta capsules compared to those taking a placebo, although these dose-response changes were not sufficient to result in significant hormonal differences between groups.  They stated that whether modest hormonal changes due to placenta supplementation are associated with therapeutic post-partum effects, however, awaits further investigation.

Young et al (2018b) performed a randomized, double-blind, placebo-controlled, pilot study (n = 27) in which participants consumed either their processed, encapsulated placenta (n = 12), or similarly prepared placebo (n = 15).  Maternal mood, bonding, and fatigue were assessed via validated scales across 4 time-points during late pregnancy and early postpartum.  Psychometric data were analyzed for changes between and within both groups over time.  No significant main effects related to maternal mood, bonding, or fatigue were evident between placenta and placebo group participants.  However, examination of individual time-points suggested that some measures had specific time-related differences between placenta and placebo groups that may warrant future exploration.  Though statistical significance should not be interpreted in these cases, these researchers did find some evidence of a decrease in depressive symptoms within the placenta group but not the placebo group, and reduced fatigue in placenta group participants at the end of the study compared to the placebo group.  The authors concluded that no robust differences in post-partum maternal mood, bonding, or fatigue were detected between the placenta and placebo groups.  This finding may be especially important for women considering maternal placentophagy as a “natural” (i.e., non-pharmacological) means of preventing or treating blues/depression.  They stated that given the study limitations, these findings should be interpreted as preliminary; small, time-related improvements in maternal mood and lower fatigue post-supplementation among placenta group participants may warrant further research.

Farr and co-workers (2018) noted that placentophagy or placentophagia, the post-partum ingestion of the placenta, is widespread among mammals; however, no contemporary human culture incorporates eating placenta post-partum as part of its traditions.  At present, there is an increasing interest in placentophagy among post-partum women, especially in the United States.  The placenta can be eaten raw, cooked, roasted, dehydrated, or encapsulated or through smoothies and tinctures.  The most frequently used preparation appears to be placenta encapsulation after steaming and dehydration.  Numerous companies offer to prepare the placenta for consumption, although the evidence for positive effects of human placentophagy is anecdotal and limited to self-reported surveys.  Without any scientific evidence, individuals promoting placentophagy, especially in the form of placenta encapsulation, claim that it is associated with certain physical and psychosocial benefits.  These investigators found that there is no scientific evidence of any clinical benefit of placentophagy among humans, and no placental nutrients and hormones are retained in sufficient amounts after placenta encapsulation to be potentially helpful to the mother post-partum.  In contrast to the belief of clinical benefits associated with human placentophagy, the Centers for Disease Control and Prevention (CDC) recently issued a warning due to a case in which a newborn infant developed recurrent neonatal group B Streptococcus sepsis after the mother ingested contaminated placenta capsules containing Streptococcus agalactiae.  The CDC recommended that the intake of placenta capsules should be avoided owing to inadequate eradication of infectious pathogens during the encapsulation process.  Therefore, in response to a woman who expresses an interest in placentophagy, physicians should inform her about the reported risks and the absence of clinical benefits associated with the ingestion.  In addition, clinicians should inquire regarding a history of placenta ingestion in cases of post-partum maternal or neonatal infections such as group B Streptococcus sepsis.  The authors concluded that there is no professional responsibility on clinicians to offer placentophagy to pregnant women.  Moreover, because placentophagy is potentially harmful with no documented benefit, counseling women should be directive: physicians should discourage this practice.   Moreover, they stated that health care organizations should develop clear clinical guidelines to implement a scientific and professional approach to human placentophagy.

Acupressure

A Canadian Thoracic Society’s clinical practice guideline on “Managing dyspnea in patients with advanced chronic obstructive pulmonary disease” (Marciniuk et al, 2011) stated that “There is insufficient evidence to support the routine use of anxiolytic medications, nebulized opioids, acupuncture, acupressure, distractive auditory stimuli (music), relaxation, handheld fans, counselling programs or psychotherapy”.

In a review on “Effects of acupressure on anxiety”, Au and co-workers (2015) stated that “Acupressure seems to be effective in providing immediate relief of pretreatment anxiety among adults, and has a medium effect size.  However, conflicting results were found for the improvements on physiological indicators.  More rigorous reporting, including allocation concealment procedure, is needed to strengthen the results”.

In a review on “The effectiveness of acupuncture, acupressure and chiropractic interventions on treatment of chronic nonspecific low back pain”, Yeganeh et al (2017) concluded that “This systematic review demonstrates that acupuncture, acupressure and chiropractic may have a favorable effect on self-reported pain and functional limitations on NSCLBP.  However, the results should be interpreted in the context of the limitations identified, particularly in relation to the heterogeneity in the study characteristics and the low methodological quality in many of the included studies”.

In a systematic review and meta-analysis of acupressure for postoperative gastrointestinal symptoms among abdominal surgery patients, Liu et al (2017) stated that “Our results suggested that acupressure might be effective in reducing the incidence of postoperative nausea and vomiting and the need for antiemetic drugs among patients undergoing abdominal surgery.  Considering the substantial risk of bias in the articles included, future high-quality RCTs with a rigorous methodology are desirable to provide solid evidence.  Furthermore, other signs and symptoms of postoperative ileus should be explored in future”.

In a systematic review on “Acupressure for respiratory allergic diseases”, Liang et al (2017) concluded that “No reliable conclusions regarding the effects of acupressure on AR (allergic rhinitis) and asthma could be drawn by this review due to the small number of available trials with significant heterogeneity of study design and high/unclear risk of bias.  Further, more rigorously designed RCTs are needed.  Acupressure seems safe for symptomatic relief of AR and asthma, although larger studies are required to be able to robustly confirm its safety”.

In a systematic review on “Acupressure effect on sleep quality”, Waits et al (2018) concluded that “Within the limitations of clinical heterogeneity, the results showed that even fragile populations such as the elderly and dialysis patients can benefit from acupressure.  Standardized treatment protocols involved 3-5 kg of pressure for 1 to 5 minutes per acupoint, delivered 3 to 7 times a week for 3 to 4 weeks with the HT7 (Shenmen) acupoint used in most procedures.  A high risk of bias due to absence of blinding of patients and personnel remains a serious methodological challenge for acupressure trials and poses a main limitation to presented results”.

In a systematic review and meta-analysis of using acupuncture and acupressure for uremic pruritus, Badiee et al (2018) concluded that “This study confirms that using acupuncture and acupressure is effective in treatment of uremic pruritus.  However, further vigorous studies are needed to verify these findings”.

In a systematic review and meta-analysis on “Auricular acupressure is an alternative in treating constipation in leukemia patients undergoing chemotherapy”, Jing et al (2019) concluded that “Taken together, as a potential safety therapy, only weak evidence supported the hypothesis that AA (auricular acupressure) effectively prevented constipation in leukemia patients undergoing chemotherapy”.

In a review on “Acupuncture or acupressure for anxiety”, Kwon and Lee (2018) concluded that ”Acupuncture or acupressure on EX-HN 3 was used mainly to reduce the anxiety of preoperative participants.  The simplicity and economics of this intervention suggest the need for future rigorous clinical trials or systematic reviews on this topic.  In addition, more experimental studies should be conducted to identify the underlying mechanisms of this anxiolytic effect”.

An UpToDate review on “Complementary and alternative therapies for allergic rhinitis and conjunctivitis” (Bielory, 2019) states that “Acupressure is similar to acupuncture but does not involve needles.  Stainless steel pellets in adhesive discs are applied to specified points (acupoints) on the ear, and the pellets are pressed firmly into the skin.  In a randomized sham-controlled trial, ear acupressure was studied for the treatment of mild to moderate perennial allergic rhinitis of 245 adults for 8 weeks with a follow-up period of 12 weeks.  Subjects were treated for 5 to 10 minutes weekly by a practitioner in a clinic and instructed to perform the therapy three times daily at home, for 10 seconds per session.  There was a small but statistically significant improvement in sneezing and quality of life in the acupressure group after 8 weeks, with additional improvements in most measures of nasal symptoms at the end of the follow-up period compared with the sham group.  These findings are interesting, although additional studies will be required to make more definitive recommendations about the utility of this therapy”.

An UpToDate review on “Nonpharmacologic approaches to management of labor pain” (Simkin and Klein, 2019) states that “Acupressure, or Shiatsu, is pressure with fingers or small beads at acupuncture points.  Limited data suggest a benefit to pressure on points Spleen 6 (located roughly on the medial surface of the low tibia) and Large Intestine 4 (located roughly on the fleshy tissue back of the hand between the base of the thumb and the base of the index finger)”.

Medical Marijuana

Nugent and colleagues (2017) reviewed the benefits of plant-based cannabis preparations for treating chronic pain in adults and the harms of cannabis use in chronic pain and general adult populations.  Data sources included Medline, Cochrane Database of Systematic Reviews, and several other sources from database inception to March 2017.  Intervention trials and observational studies, published in English, involving adults using plant-based cannabis preparations that reported pain, quality of life (QOL), or adverse effect outcomes were selected for analysis.  Two investigators independently abstracted study characteristics and assessed study quality, and the investigator group graded the overall strength of evidence using standard criteria.  From 27 chronic pain trials, there was low-strength evidence that cannabis alleviates neuropathic pain but insufficient evidence in other pain populations.  According to 11 systematic reviews and 32 primary studies, harms in general population studies include increased risk for motor vehicle accidents, psychotic symptoms, and short-term cognitive impairment.  Although adverse pulmonary effects were not seen in younger populations, evidence on most other long-term physical harms, in heavy or long-term cannabis users, or in older populations is insufficient.  The authors concluded that limited evidence suggested that cannabis may alleviate neuropathic pain in some patients, but insufficient evidence exists for other types of chronic pain.  Among general populations, limited evidence suggested that cannabis is associated with an increased risk for adverse mental health effects.  The main drawbacks of this study were:

1. few methodologically rigorous trials,
2. the cannabis formulations studied may not reflect commercially available products, and
3. limited applicability to older, chronically ill populations and patients who use cannabis heavily.

O'Neil and associates (2017) identified ongoing studies and review existing evidence regarding the benefits and harms of plant-based cannabis preparations in treating post-traumatic stress disorder (PTSD) in adults.  Data sources included Medline, the Cochrane Library, and other sources from database inception to March 2017.  English-language systematic reviews, trials, and observational studies with a control group that reported PTSD symptoms and adverse effects of plant-based cannabis use in adults with PTSD were selected for analysis.  Study data extracted by 1 investigator was checked by a 2nd reviewer; 2 reviewers independently assessed study quality, and the investigator group graded the overall strength of evidence by using standard criteria.  Two systematic reviews, 3 observational studies, and no randomized trials were found.  The systematic reviews reported insufficient evidence to draw conclusions about benefits and harms.  The observational studies found that compared with non-use, cannabis did not reduce PTSD symptoms.  Studies had medium and high risk of bias, and overall evidence was judged insufficient.  Two randomized trials and 6 other studies examining outcomes of cannabis use in patients with PTSD are ongoing and are expected to be completed within 3 years.  The authors concluded that evidence is insufficient to draw conclusions about the benefits and harms of plant-based cannabis preparations in patients with PTSD, but several ongoing studies may soon provide important results.  The main drawback of this study was very scant evidence with medium-to-high risk of bias.

Acute Respiratory Tract Infection in Children

Lucas and colleagues (2018) noted that as many as 1 in 2 children across the globe use complementary and alternative medicine (CAM) to manage a health condition.  Despite the high prevalence of use, there is still limited information on the types of CAM used in children, particularly for the management of one of the most common childhood health complaints -- acute respiratory tract infection (ARTI).  This systematic review was undertaken to address this knowledge gap.  Eligible studies reporting the use of CAM in children with ARTI were identified using a targeted search of 7 electronic databases and the grey literature.  Data were extracted using a customized data extraction form and appraised using the McMaster critical review forms for quantitative and qualitative studies.  Findings were synthesized in narrative form.  The search identified 2,261 papers, of which 22 studies were eligible for inclusion.  The 22 studies reported the use of 118 distinct CAM interventions for the management of ARTI in children.  Most (53 %, n = 63) of these interventions represented biologically-based therapies, followed by whole medical systems/alternative medical systems (46 %, n = 55).  No studies reported the use of energy therapies, or manipulative and body-based methods, or mind-body therapies.  The authors concluded that a variety of CAM interventions are used in the management of ARTI in children.  These interventions largely represent CAM use in the Southern region of Asia - India, Pakistan and Bangladesh.  These researchers stated that further research is needed to better understand the types of CAM used among children with ARTI in Western countries.

Chronic Rhinosinusitis

Griffin and colleagues (2018) stated that the use of alternative medicine in chronic rhinosinusitis (CRS) continues to increase in popularity, for the most part without meeting the burden of being based on sound clinical evidence.  New and emerging treatments, both natural and developed, are numerous, and it remains a challenge for otolaryngologists as well as general practitioners to keep up-to-date with these therapies and their efficacy.  In a systematic review, these investigators discussed a number of alternative therapies for CRS, their proposed physiologic mechanisms, and evidence supporting their use.  This analysis was based on their review of the English-language literature on alternative therapies for CRS (they did not include any therapies that were already recommended by accepted professional bodies).  Data collection was performed using the PubMed database (not restricted to Medline due to the nature of the subject matter), the Cochrane databases, and bibliography searches.  These researchers found that while many of the alternative therapies they reviewed might have a firm basis in science, they lacked any clinical evidence to support their use specifically for CRS.  Some emerging therapies, such as therapeutic ultrasonography (US) and phonophoresis, showed some promise, based on a growing body of positive evidence.  Furthermore, the use of baby shampoo, thyme honey, and bromelain additives to saline lavage in CRS are all supported by clinical evidence, as is Sinupret, an oral preparation that contains echinacea.  However, the authors concluded that higher levels of evidence gleaned from large, well-designed, prospective, RCTs are needed before any of these therapies could be recommended.

In a systematic review and qualitative analysis, Jin and Chin (2018) evaluated the evidence for CAM use in CRS through a systematic review of current literature that examined the effects of CAM on symptoms and clinical status of adults with CRS.  These investigators carried out a comprehensive systematic review of the literature using 5 databases from inception to July 2017: CINAHL, Cochrane, Embase, PubMed, and SCOPUS.  Inclusive medical subject headings and keywords consisted of, but were not limited to, sinusitis and complementary therapies, naturopathy, or traditional Chinese medicine.  PRISMA guideline was followed.  Using templates by Cochrane Public Health Group and Newcastle-Ottawa Scale, each author extracted data, assessed bias, and computed minimal clinically important difference.  Any conflicts were resolved through discussion.  In total, 7 of 7,141 articles from 1995 to 2016 were included; 3 RCTs and 4 observational studies were organized into 4 categories of CAM: naturopathy, Chinese medicine, homeopathy, and others.  Limited evidence supported the use of Pimpinella anisum and crenotherapy for CRS.  Data available on Chinese medicine, homeopathy, and liposomal therapy in CRS were inconclusive due to inherent flaws in the studies.  The authors concluded that overall, there is very limited evidence to support the use of CAM in the treatment of CRS.  No significant adverse events (AEs) have been found.  These researchers stated that given its widespread use, more rigorous data from high-quality research are needed before it can be routinely recommended.

Endometriosis

Mira and colleagues (2018) identified resources, methods, and/or complementary treatments to alleviate the pain symptoms of endometriosis, and reported AEs of treatments.  Lilacs, Scielo, PEDro, Scopus, PubMed, CENTRAL Cochrane, Science Direct, and Google Scholar were searched for studies published in Portuguese, English, and Spanish to July 31, 2017, using the terms "physical therapy" or "complementary treatment" and "endometriosis"; RCTs relating to complementary pelvic pain treatment and AEs were selected for analysis.  A total of 8 studies were identified; 2 studies were included in the meta-analysis.  The complementary interventions studied were acupuncture, exercise, electrotherapy, and yoga.  All were inconclusive in affirming benefit, but demonstrated a positive trend in the treatment of symptoms of endometriosis.  Meta-analysis of acupuncture showed a significant benefit in pain reduction as compared with placebo (p = 0.007).  The authors concluded that numerous complementary treatments have been used to alleviate the symptoms of endometriosis, but only acupuncture has demonstrated a significant improvement in outcomes.  Nevertheless, other approaches demonstrated positive trends toward improving symptoms; this should encourage investigators to design controlled studies to support their applicability.

Furthermore, an UpToDate review on “Endometriosis: Treatment of pelvic pain” (Schenken, 2019) states that “In a systematic review of acupuncture for treatment of endometriosis-related pain, only one randomized trial met the inclusion criteria.  In that trial (n = 67), auricular acupuncture was significantly more effective than Chinese herbal medicine for treating dysmenorrhea in women with endometriosis”.

Generalized Anxiety Disorder

In a systematic review, Baric  and colleagues (2018) examined the safety and efficacy of CAM for the treatment of generalized anxiety disorder (GAD) based on RCTs in adults.  A total of 6 electronic databases ("generalized anxiety (disorder)" and "randomized trial") and reference lists of identified publications were searched to March 2017.  Full-text publications (English, German language); CAM versus conventional treatment, placebo/sham or no treatment; GAD diagnosed according to standard criteria; and a validated scale for disease severity were eligible for selection.  Of the 6,693 screened records, 32 were included (18 on biologically-based therapies, exclusively herbal preparations; 8 on manipulative and body-based therapies; and 3 on alternative medical systems and 3 on mind-body therapies).  Cochrane Collaboration methodology was used for quality assessment and data extraction.  Direct comparisons of Kava Kava (Piper methysticum) extracts to placebo (4 quality trials, n = 233) were highly heterogeneous.  Network meta-regression reduced heterogeneity and suggested a modest Kava effect [end-of-treatment Hamilton Anxiety scale score difference adjusted for baseline scores and trial duration: - 3.24 (95 % CI: - 6.65 to 0.17; p = 0.059), Kava Kava 4 arms, n = 139; placebo 5 arms, n = 359].  Lavender (Lavandula angustifolia) extract (1 quality trial, 10 weeks, n = 523) and a combination of extracts of C. oxycantha, E. californica and magnesium (1 quality trial, 12 weeks, n = 264) were superior to placebo, and balneotherapy was superior to paroxetine (1 quality trial, 8 weeks, n = 237) indicating efficacy.  All other trials were small and/or of modest/low quality and/or lacked assay sensitivity.  Safety reporting was poor.  The authors concluded that evidence regarding the safety and efficacy of most CAM methods in GAD is limited.  Apparent efficacy of certain herbal preparations and body-based therapies requires further confirmation.

Intravenous Ascorbic Acid (Compounded) for Malnutrition from Chronic Pancreatitis

The National Pancreas Foundation’s webpage on “Acute Pancreatitis risks and treatment” (2020) stated that “Basic and clinical evidence suggests that the development of both acute pancreatitis (AP) and chronic pancreatitis (CP) can be associated with oxidative stress.  Findings show that free radical activity and oxidative stress indices are higher in the blood and duodenal juice of patients with pancreatitis.  Based on these findings, the idea of using antioxidant regimens in the management of both AP and CP as a supplement and complementary in combination with its traditional therapy is reasonable.  In practice, however, the overall effectiveness of antioxidants is not known, and the best mixture of agents and dosages is not clear.  Currently, a trial of a mixture of antioxidants containing vitamin C, vitamin E, selenium, and methionine is reasonable as one component of overall medical management.  In summation, there is no definite consensus on the dosage, length of therapy, and ultimately, the benefits of antioxidant therapy in the management of AP or CP.  Further well-designed clinical studies are needed to determine the appropriate combination of agents, time of initiation, and duration of therapy”.

Patricia Kane (PK) Protocol

Dr. Patricia Kane brought the PK Protocol from Europe to the United States to help treat neurological illnesses including Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), autism, cancer, chronic Lyme disease, epilepsy, mold & chemical toxicity, mood disorders, motor neuron disease, multiple sclerosis, Parkinson’s disease, and many others.  These IV infusions mainly consist of phosphatidylcholine, with syringe pushes of leucovorin, glutathione and a shot of vitamin B12.  It can be administered as much as one can handle, and is slowly reduced as the cells heal.  However, there is a lack of evidence regarding the clinical value of the PK Protocol.

Spascupreel Injection Solution

Spascupreel Injection Solution is a homeopathic drug indicated for the relief of spasms of the smooth musculature of the gastro-intestinal (GI) and the urogenital tract as well as general muscle spasms.  Each 1.1-ml ampule contains Aconitum napellus, Agaricus muscarius, ammonium bromatum, atropinum sulphuricum, Chamomilla, Colocynthis, Cuprum sulphuricum, Gelsemium sempervirens, magnesia phosphorica, Passiflora incarnata, and Veratrum album.  Spascupreel may be administered in any of the following manner: intra-dermal (ID), intra-muscular (IM), IV, or subcutaneous (SC).

Muller-Krampe and colleagues (2007) noted that GI spasms and cramps are common in children as well as in adults.  Alternative medical practices such as chiropractic and homeopathy are becoming increasingly popular in Europe and the United States.  The effectiveness and tolerability of the homeopathic preparation Spascupreel (SP-11)was compared with that of hyoscine butylbromide treatment in children less than 12 years of age.  These researchers carried out an observational cohort study of 204 children less than 12 years over a 1-week treatment period.  The efficacy of the respective therapies were evaluated on the effect on severity of spasms and clinical symptoms (pain/cramps, sleep disturbances, distress, eating or drinking difficulties and frequent crying).  Compliance was evaluated on a 4-point scale from “very good” to “low”.  Evaluation was performed by the practitioner based on information given by the patient or care-giver.  The analysis showed comparative improvements with the homeopathic preparation and hyoscine butylbromide therapy on severity of spasms, pain/cramps, sleep disturbances, eating or drinking difficulties, and frequent crying, all as evaluated by the practitioner.  Both treatments were very well-tolerated.  The authors concluded that for patients opting for a homeopathic therapy, SP-11 appeared to be an effective and well-tolerated alternative to conventional therapies in children suffering from GI spasms.  This was an observation, single-center study; its findings need to be validated by well-designed studies. 

Theodorou and associates (2020) noted that irritable bowel syndrome (IBS) is a common disorder worldwide.  It is characterized by abdominal pain / discomfort and changes in bowel habits.  Due to the multi-factorial pathophysiology and the heterogeneity of IBS patients, appropriate treatment of IBS is still a challenge.  Spascupreel, as a multi-component medication, has the potential to modulate multiple pathophysiological pathways simultaneously.  These investigators examined the effects of oral SP-11 treatment on stress-induced changes of peripheral and central functions in a rat model mimicking human IBS.  Naïve Wistar rats were treated with SP-11 (0.9 tab/kg) or NaCl 0.9 % by oral gavage for 4 days before 2-hour partial restraint stress (PRS) procedure.  Twenty minutes after PRS, central and peripheral stress-induced changes affecting IBS were assessed.  These included the hypothalamic-pituitary-adrenal (HPA) axis response through plasma adrenocorticotropic hormone (ACTH) and corticosterone measurements, visceral pain in response to colorectal distension, gut permeability, colonic mast cell number, and sensitization as well as gut transit time.  Treatment with SP-11 reduced the HPA axis activation in response to PRS.  At the gut level, a reduction in colonic hypersensitivity to colorectal distension, a normalization of gut transit time acceleration, a reduced mast cell sensitization, and a trend toward reduced gut hyperpermeability were observed.  The authors concluded that these findings suggested that stress-induced IBS signs can be reduced using SP-11 in rats.  The observed effects and the good tolerability of the drug made SP-11 an innovative candidate in the management of IBS.

Transverse Friction Massage (Also Known as Cross-Friction and Cross-Fiber Massage)

Zalta (2008) determined the effectiveness of massage therapy in the rehabilitation of post-anterior cruciate ligament (ACL) reconstruction patella-femoral pain syndrome (PFPS).  The primary complications following surgical repair of the ACL -- classified as PFPS -- are hamstring flexion contracture and quadriceps weakness, leading to patella-femoral dysfunction and retro-patellar pain.  Treatment included lymphatic drainage, myofascial release, neuromuscular techniques including trigger-point release, muscle energy techniques and cross-fiber friction.  Orthopedic physical assessment tests were used to chart changes in patella-femoral function and changes in ROM in the knee during the course of the massage interventions.  Subjective reporting on pain level and function were also documented.  A decrease in pain level, hamstring flexion contracture and lateral tracking of the patella were documented.  The author concluded that massage therapy was determined to be an effective complementary therapy in the treatment of PFPS.  This was a single-case study; and its findings were confounded by the use of multiple modalities.

Romanowski et al (2012) compared the effectiveness of 2 different kind of massage: therapeutic massage (TM), and deep tissue massage (DTM) on chronic LBP.  The research was made on 26 patient aged from 60 to 75 years who were separated into 2 groups: I (n = 13) and II (n = 13).  Group I had TM that uses effleurage, petrissage, tapping and friction.  Group II had DTM that uses oblique pressure, a combination of lengthening and cross-fiber strokes, anchor and stretch, freeing muscle from entrapment.  Both TM and DTM lasted for 10 days, each 30 mins and were made by qualify massage therapist.  Both groups did not have other treatment.  Outcome measures obtained at baseline and after treatment consisted of Modified Oswestry LBP Disability Index [ODI], Quebec Back Pain Disability Scale [QBPD] and VAS.  There were no statistically significant differences between groups according to age and body mass index (BMI).  Statistically significant differences were noted after TM in every test [ODI p = 0.010; QBPD p < 0.001; VAS p < 0.001] and after DTM in every test [ODI p < 0.001; QBPD p < 0.001; VAS p < 0.001].  Deep tissue massage was statistically significant better therapy than TM in ODI [p = 0.038] and VAS [p = 0.015].  Moreover, they stated that further research is needed to verify these findings.

Streit (2014) stated that neurogenic thoracic outlet syndrome (NTOS) is a neuromuscular condition affecting brachial plexus functionality.  NTOS is characterized by paresthesia, pain, muscle fatigue, and restricted mobility in the upper extremity (UE).  This investigator quantified massage therapy (MT)'s possible contribution to treatment of NTOS.  The author reported on the case of a 24-year old woman with NTOS who received 8 treatments over 35 days.  Treatment included myofascial release, trigger-point therapy, cross fiber friction (XFF), muscle stripping, and gentle passive stretching.  Abduction and lateral rotation at the gleno-humeral (GH joint) assessments measured ROM.  A resisted muscle test evaluated UE strength.  The client rated symptoms daily via a VAS.  Findings showed improvement in ROM at the GH joint; VAS ratings revealed a reduction in muscle weakness, pain, numbness, and “paresthesia”.  The author concluded that these findings suggested that MT may be useful as part of a broad approach to managing NTOS symptoms and improving mobility.

Exosome Therapy

Urbanelli et al (2015) noted that exosomes are small extracellular vesicles (EVs; 30 to 120 nm) of endosomal origin, which are gaining the attention of the scientific community.  Originally considered only a waste disposal system, they are now emerging as another class of signal mediators.  Exosomes are secreted by any cell type and retrieved in every body fluid, such as blood, urine, saliva and amniotic liquid.  Remarkably, their biochemical content includes not only lipids and proteins, but also nucleic acids, mainly miRNA and mRNA, with a few reports also indicating the presence of genomic and mitochondrial DNA.  Their properties have stimulated extensive research to exploit them as a source of biomarkers for the diagnosis and the follow-up of several pathologies.  Furthermore, exosomes are relatively robust and stable, so they appear attractive as gene and drug delivery vehicles.  They have also revealed immunomodulatory and regenerative properties, which are encouraging their application for therapeutic purposes.  Several issues remain to be addressed: exosome isolation is still time-consuming and unsatisfactorily reproducible, making it difficult to compare results among laboratories, improve the knowledge of their physiological function and correlate their features with pathological outcomes.  Nevertheless, the number of patents trying to address these problems is growing exponentially and many novelties will reach the scientific community in the next few years.

Tao et al (2017) noted that osteoarthritis (OA) is the most common joint disease throughout the world.  Exosomes derived from miR-140-5p-over-expressing synovial mesenchymal stem cells (SMSC-140s) may be effective in treating OA.  These researchers hypothesized that exosomes derived from SMSC-140 (SMSC-140-Exos) would enhance the proliferation and migration abilities of articular chondrocytes (ACs) without harming extra-cellular matrix (ECM) secretion.  SMSCs were transfected with or without miR-140-5p.  Exosomes derived from SMSCs or SMSC-140s (SMSC-Exos or SMSC-140-Exos) were isolated and identified.  Proliferation, migration and ECM secretion were measured in-vitro and compared between groups.  The mechanism involving alternative Wnt signaling and activation of Yes-associated protein (YAP) was investigated using lentivirus, oligonucleotides or chemical drugs.  The preventative effect of exosomes in-vivo was measured using Safranin-O and Fast green staining and immunohistochemical staining.  Wnt5a and Wnt5b carried by exosomes activated YAP via the alternative Wnt signaling pathway and enhanced proliferation and migration of chondrocytes with the side-effect of significantly decreasing ECM secretion.  Highly-expressed miR-140-5p blocked this side-effect via RalA.  SMSC-140-Exos enhanced the proliferation and migration of ACs without damaging ECM secretion in-vitro, while in-vivo, SMSC-140-Exos successfully prevented OA in a rat model.  The authors concluded that these findings highlighted the promising potential of SMSC-140-Exos in preventing OA.  These investigators first found a potential source of exosomes and studied their merits and shortcomings.  Based on their understanding of the molecular mechanism, these researchers overcame the shortcomings by modifying the exosomes.  Such exosomes derived from modified cells hold potential as future therapeutic strategies.

Campanella et al (2019) stated that EVs are lipid membrane vesicles released by all human cells and are widely recognized to be involved in many cellular processes, both in physiological and pathological conditions.  They are mediators of cell-cell communication, at both paracrine and systemic levels; thus, they are active players in cell differentiation, tissue homeostasis, and organ re-modeling.  Due to their ability to serve as a cargo for proteins, lipids, and nucleic acids, which often reflects the cellular source, they should be considered the future of the natural nano-delivery of bio-compounds.  To-date, natural nano-vesicles, such as exosomes, have been shown to represent a source of disease biomarkers and have high potential benefits in regenerative medicine.  Indeed, they deliver both chemical and bio-molecules in a way that within exosomes drugs are more effective that in their exosome-free form.  Therefore, to-date, it is known that exosomes are shuttle disease biomarkers and probably the most effective way to deliver therapeutic molecules within target cells.  However, it is unclear exactly which exosomes may be used in therapy in avoiding side effects as well.  In regenerative medicine, it will be ideal to use autologous exosomes, but it appeared not ideal to use plasma-derived exosomes, as they may contain potentially dangerous molecules.  The authors presented a contradictory relatively unmet issue that is the lack of a general agreement on the choice for the source of EVs for therapeutic use.

Fang and Vangsness (2020) stated that EVs released from cells that are a part of many biological and pathological processes, especially in intercellular communication. These vesicles are involved cell signaling, influence tissue and immune response, and serve as biomarkers for diseases.  Most interesting are the exosomes that are released from MSCs for inflammation in joint diseases.  Preliminary studies have demonstrated the advantages of using EVs rather than MSCs for cell free therapy.  Research on exosomes have shown promising results as biomarkers for tracking the pathogenesis and prognosis of inflammatory arthritis.  Therapeutically, animal studies have demonstrated immunosuppression, reversing inflammation, increasing chondrocyte proliferation, and drug delivery properties.  The author concluded that the field of exosomes continues to develop and more basic science and clinical studies with safety and efficacy studies are needed.

Injection of Vitamin B and Trace Elements for the Treatment of Chronic Pain Syndrome

UpToDate reviews on “Approach to the management of chronic non-cancer pain in adults” (Tauben and Stacey, 2021a), and “Pharmacologic management of chronic non-cancer pain in adults” (Tauben and Stacey, 2021b) do not mention injection of vitamin B and trace elements as a management / therapeutic options.

Intravenous Curcumin Infusion for the Treatment of Cancers

Saghatelyan and colleagues (2020) stated that the clinical efficacy of curcumin has not yet been established for the treatment of cancer, despite a large body of evidence from numerous pre-clinical studies suggesting the therapeutic potential of curcumin, especially when combined with paclitaxel.  The main obstacle in using curcumin for adjunctive cancer therapy is its low bioavailability via oral administration.   In a randomized, double-blind, placebo-controlled, parallel-group comparative clinical trial, these researchers examined the safety and efficacy of intravenous curcumin infusion in combination with paclitaxel in patients with metastatic and advanced breast cancer.  A total of 150 women with advanced and metastatic breast cancer were randomly assigned to receive either paclitaxel (80 mg/m2) plus placebo or paclitaxel plus curcumin (CUC-1, 300 mg solution, once-weekly) intravenously for 12 weeks with 3 months of follow-up.  The primary outcome was determined based on the objective response rate (ORR), as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST).  The secondary outcomes were progression-free survival (PFS), time to tumor progression (TTP), time to tumor treatment failure (TTTF), safety, and quality of life.  The intention-to-treat (ITT) analysis revealed that the ORR of curcumin was significantly higher than that of the placebo (51 % versus 33 %, p < 0.01) at 4 weeks of follow-up.  The difference between the groups was even greater when only patients who had completed the treatment (61 % versus 38 %, odds ratio [OR] = 2.64, p < 0.01) were included.  A superior effect of curcumin versus placebo was observed in both patients who had completed the treatment and all patients included in the ITT analysis, 3 months after termination of the treatment.  No other significant differences were observed between the curcumin and the placebo groups, except for fatigue (3 versus 10 patients, respectively; OR = 3.7, p = 0.05).  However, the patients' self-assessed overall physical performance was significantly higher with curcumin than the placebo during the treatment and at the end of the follow-up, suggesting better tolerance in the curcumin group.  The authors concluded that treatment with curcumin in combination with paclitaxel was superior to the paclitaxel-placebo combination with respect to ORR and physical performance after 12 weeks of treatment.  Intravenously administered curcumin caused no major safety issues and no reduction in QOL, and it may be beneficial in reducing fatigue.  This was the first clinical trial that examined the safety and efficacy of administering curcumin intravenously in combination with chemotherapy in the treatment of cancer patients.

Troselj and co-workers (2020) stated that most data published on curcumin and curcumin-based formulations are very promising.  In cancer research, the majority of data has been obtained in-vitro; less frequently, researchers used experimental animals.  The results of several clinical studies were conclusive, and these studies have established a good foundation for further research focusing on implementing curcumin in clinical oncology; however, the issues regarding timely data reporting and lack of disclosure of the exact curcumin formulations used in these studies should not be neglected.  These researchers provided a review of the current status of publicly available data on curcumin clinical trials and a detailed presentation of results obtained so far with some curcumin formulations.  Phenomena related to the observed effects of curcumin shown in clinical trials were presented, and its modifying effect on gut microbiota and metabolic re-programming was discussed.  The authors concluded that based on available data, there is a strong indication that curcumin and its metabolites present molecules that do not necessarily need to be abundant in order to act locally and benefit systemically; and future clinical trials should be designed in a way that will take that fact into consideration.

Fabianowska-Majewska and associates (2021) noted that one of the most systematically studied bioactive nutraceuticals for its benefits in the management of various diseases is the turmeric-derived compounds: curcumin.  Curcumin is well known for its potential role in inhibiting cancer by targeting epigenetic machinery, with DNA methylation at the forefront.  The dynamic DNA methylation processes serve as an adaptive mechanism to a wide variety of environmental factors, including diet.  Every healthy tissue has a precise DNA methylation pattern that changes during cancer development, forming a cancer-specific design.  Hypermethylation of tumor suppressor genes, global DNA demethylation, and promoter hypomethylation of oncogenes and pro-metastatic genes are hallmarks of nearly all types of cancer, including breast cancer.  Curcumin has been shown to modulate epigenetic events that are dysregulated in cancer cells and possess the potential to prevent cancer or enhance the effects of conventional anti-cancer therapy.  Although mechanisms underlying curcumin-mediated changes in the epigenome remain to be fully elucidated, the mode of action targeting both hyper-methylated and hypo-methylated genes in cancer is promising for cancer chemoprevention.  The authors provided a comprehensive discussion of potential epigenetic mechanisms of curcumin in reversing altered patterns of DNA methylation in breast cancer that is the most commonly diagnosed cancer and the leading cause of cancer death among women worldwide.

These researchers stated that curcumin showed promising chemo-preventive effects in the laboratory experiments; however, its clinical application is still limited because of low water solubility and low metabolic stability.  Nevertheless, the numerous studies undergoing in various laboratories and clinics intensively working on evolving novel phytochemical-based therapeutic options for breast cancer implies that phytochemicals such as curcumin are the leading molecules for future anti-cancer drug development targeting breast cancer-related signaling pathways.  Moreover, the effective doses of curcumin have not been shown to exert any toxicities or side effects making this bioactive compound ideal preventative and anti-cancer agent.  Therefore, the principal challenges in the examination of curcumin as an epigenetic anti-cancer agent are new strategies of increasing its bioavailability, evaluating the efficacy of the metabolites and determining the role of this phytochemical alone or in combination with other turmeric-derived compounds and existing drugs in improving anti-cancer efficacy.  These important issues should be addressed in future nutria-epigenomic studies.  These investigators stated that while there is much more to be done, the available data so far indicate that curcumin can be a potential target of drug development against cancer.

Intravenous Magnesium for the Treatment of Fibromyalgia

Wilderman et al (2020) conducted a retrospective chart review of 74 patients diagnosed with fibromyalgia (FM) who underwent at least 3 escalating doses of intravenous (IV) lidocaine infusions (5 mg/kg of body weight, 7.5 mg/kg, and 7.5 mg/kg of lidocaine + 2.5 g of magnesium sulfate).  Each patient's subjective impression of change in pain intensity and duration of pain relief after each treatment was recorded, along with an 11-point numeric rating scale (NRS) for pain intensity, immediately before and after each infusion.  Short-term lidocaine analgesia was examined by the reduction in NRS pain score according to the patients reported pre- (immediately before treatment) and post-treatment (immediately after treatment) values.  There was a statistical difference in the NRS score reduction between doses 5 mg/kg and 7.5 mg/kg of lidocaine (p = 0.009).  Long-term analgesia was examined at follow-up visits by the patient's subjective impression of change in pain intensity and duration of pain relief.  There was a statistical difference in the percentage of pain relief and the mean duration of pain relief between the treatments with 5 mg/kg and 7.5 mg/kg of lidocaine (p = 0.007 and p = 0.003).  Although there was a trend of greater response to magnesium sulfate as a beneficial adjunct to the lidocaine infusion, these researchers were unable to find a statistically significant difference for any of the variables studied.  The authors concluded that the findings of this study demonstrated that escalating doses of IV lidocaine to 7.5 mg/kg safely and effectively reduced the pain with prolonged effect in a significant number of patients diagnosed with FM.  Moreover, these researchers stated that larger, prospective clinical studies are needed to confirm these findings.

Furthermore, UpToDate reviews on “Initial treatment of fibromyalgia in adults” (Goldenberg, 2021a) and “Treatment of fibromyalgia in adults not responsive to initial therapies” (Goldenberg, 2021b) do not mention intravenous magnesium as a therapeutic option.

Pharmaco-Puncture (Herbal Acupuncture)

Pharmaco-puncture is a relatively new form of acupuncture combining acupuncture with herbal medicine, and it has been used under various conditions in Korea.  Currently, there is inadequate evidence supporting the use of pharmaco-puncture.

Cheon et al (2014) stated pharmaco-puncture, injection to acupoints with pharmacological medication or herbal medicine, is a new acupuncture therapy widely available in Korea and China for cancer-related symptoms; however, the evidence is still unclear.  These researchers examined the effectiveness of pharmaco-puncture on cancer-related symptoms.  A total of 11 databases were searched for RCTs of pharmaco-puncture in cancer patients.  The Cochrane risk of bias (ROB) assessment tool was used for quality assessment.  A total of 22 studies involving 2,459 patients were included; 5 trials of chemotherapy-induced nausea and vomiting (CINV) underwent meta-analysis.  Pharmaco-puncture significantly relieved severity of CINV compared with control group (3 trials, RR 1.28, 95 % CI: 1.14 to 1.44).  The frequency of CINV was also significantly reduced with pharmaco-puncture (2 trials, RR 2.47, 95 % CI: 2.12 to 2.89); 17 trials studied various symptoms, and in most studies, pharmaco-puncture significantly relieved pain, ileus, hiccup, fever, and GI symptoms and improved QOL in various cancer patients; ROB was generally high.  The authors concluded that it may be suggested with caution that pharmaco-puncture may help various symptom relief in cancer patients; however, it is hard to draw a firm conclusion due to clinical heterogeneity and high ROB of the included studies, hence warranting further investigation.

Park et al (2016) noted that pharmaco-puncture is a new form of acupuncture combining acupuncture with herbal medicine, and it has been used under various conditions in Korea.  These investigators examined clinical evidence for the safety and efficacy of pharmaco-puncture in Korea.  They searched 9 databases and 2 relevant journals up to December 2014 using keywords, such as pharmaco-puncture.  All RCTs evaluating pharmaco-puncture under any conditions in Korea were considered.  A total of 29 studies involving 1,211 participants were included.  A meta-analysis of 2 studies on obesity showed that 5 to 8 weeks of pharmaco-puncture reduced weight, waist circumference, and BMI more than normal saline injections.  In the 5 studies of musculoskeletal conditions, 7 to 30 days of pharmaco-puncture had additional effects on the reduction of pain intensity, and this benefit was maintained by limiting analyses to studies with a low risk of bias for randomization and/or allocation concealment.  The authors concluded that the findings of this systematic review suggested the potential of pharmaco-puncture for obesity and musculoskeletal diseases; however, it is difficult to recommend pharmaco-puncture as an evidence-based treatment because of methodological flaws and small sample sizes of the included studies.  These researchers stated that further well-designed trials are needed to draw a definitive conclusion.

Cho et al (2018) stated that pharmaco-acupuncture is a new acupuncture treatment that stimulates acupuncture points by injecting herbal medicine into them.  Recently, pharmaco-acupuncture has been widely used in the treatment of idiopathic Parkinson's disease (PD) in traditional East Asian medicine.  In a systematic review, these investigators examined the safety and efficacy of pharmaco-acupuncture in the treatment of idiopathic PD.  The following electronic databases were searched for studies published in or before December 2016: Medline, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, OASIS, and CNKI, without language restriction.  The main outcome assessed was the total Unified Parkinson's Disease Rating Scale (UPDRS) score.  The details of the pharmaco-acupuncture intervention, such as the herbal medicine and acupuncture points used, were also investigated.  From 138 studies, 3 RCTs were included; the number of patients analyzed was 134.  Most of the studies showed considerable methodological flaws.  There was heterogeneity of the intervention type and treatment duration in the included studies; thus, these researchers could not perform a meta-analysis.  In 1 study, adjunctive bee venom pharmaco-acupuncture therapy significantly improved total UPDRS scores compared with conventional therapy alone.  Another study, which used adjunctive Kakkonein pharmaco-acupuncture, did not reveal significant improvement compared with conventional therapy alone.  A 3rd study reported that Mailuoning pharmaco-acupuncture was able to significantly improve the modified Webster Symptom Score when compared with no treatment; AEs related to the pharmaco-acupuncture were reported in only 1 case, itching caused by the bee venom.  The authors concluded that the findings of this systematic review regarding the efficacy of pharmaco-acupuncture as a therapy for idiopathic PD are currently inconclusive.  These researchers stated that further large and rigorous clinical trials are needed.

Choi and Kim (2019) stated that hot flashes are the most frequent symptoms of the menopause, with 10 to 20 % of all post-menopausal women reporting nearly intolerable occurrences.  Although pharmaco-puncture with hominis placenta extract (PLC) is one of the new acupuncture therapies popular in East Asian medicine with a known efficacy in treating facial flushing, there has been little research on the safety and efficacy of this extract.  Thus, this study aims to examine the safety and efficacy of pharmaco-puncture with hominis PLC compared to injections of normal saline, in peri- and post-menopausal women in Korea.  This study is a randomized, placebo-controlled, single-blind, multi-center, parallel-design trial.  A total of 128 peri- or post-menopausal women who meet the inclusion criteria will be recruited.  The treatment group will receive PLC pharmaco-puncture twice-weekly, for a total of 18 sessions over 9 weeks.  The control group will receive injections of normal saline at the same acupoints during the same period.  The post-treatment follow-up evaluation will occur 4 weeks after the subject has completed the treatment.  The authors concluded that they believe that this trial will provide evidence on the safety and efficacy of PLC pharmaco-puncture as a treatment for hot flashes in per- and post-menopausal women.

Hwang et al (2020) stated musculoskeletal disorders are the main reason for individuals to seek counseling and use of CAM.  Although pharmaco-puncture is used to treat various diseases in traditional medicine, it is most often used in the treatment of musculoskeletal conditions.  These investigators will review systematically the clinical evidence for the safety and effectiveness of pharmaco-puncture for musculoskeletal diseases.  A total of 13 databases will be searched for studies up-loaded from January 2014 to December 2018 that examined the treatment of musculoskeletal diseases.  These databases are Medline, Embase, AMED, Cochrane Library, CINAHL, 4 Korean databases, 2 Chinese database, and 2 Japanese databases.  The methodological quality of RCTs will be analyzed using the Cochrane Collaboration tool to evaluate risk of bias, and the confidence in the cumulative evidence will be assessed using the GRADE instrument.  This systematic review will be published in a peer-reviewed journal and disseminated electronically and in print.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes not covered for indications listed in the CPB:
Acoustic therapy for anxiety/depression, Colonic cleansing / colon hydrotherapy, augmented soft tissue mobilization (ASTM), intravenous ascorbic acid (compounded), Spascupreel injection solution, supportive oligonucleotide technique (SOT) - no specific code:
86353	Lymphocyte transformation, mitogen (phytomitogen) or antigen induced blastogenesis [total antioxidant function testing, e.g., Spectrox]
90880	Hypnotherapy
96360	Intravenous infusion, hydration; initial 31 minutes to 1 hour [not covered for intravenous micronutrient therapy (Myers' Cocktail) or Vitamin C infusions]
96900	Actinotherapy (ultraviolet light) [Biophotonic Therapy]
Other CPT codes related to the CPB:
20974	Electrical stimulation to aid bone healing; noninvasive (nonoperative)
20975	invasive (operative)
64550	Application of surface (transcutaneous) neurostimulator
82136	Amino acids, 2 to 5 amino acids, quantitative, each specimen [micronutrient]
82180	Ascorbic acid (Vitamin C), blood [micronutrient]
82306	Vitamin D; 25 hydroxy, includes fraction(s), if performed [micronutrient]
82310	Calcium; total [micronutrient]
82379	Carnitine (total and free), quantitative, each specimen [micronutrient]
82495	Chromium [micronutrient]
82525	Copper [micronutrient]
82607	Cyanocobalamin (Vitamin B-12) [micronutrient]
82652	Vitamin D; 1, 25 dihydroxy, includes fraction(s), if performed [micronutrient]
82725	Fatty acids, nonesterified [micronutrient]
82746	Folic acid; serum [micronutrient]
82978	Glutathione [micronutrient]
83735	Magnesium [micronutrient]
83785	Manganese [micronutrient]
84207	Pyridoxal phosphate (Vitamin B-6) [micronutrient]
84252	Riboflavin (Vitamin B-2) [micronutrient]
84255	Selenium [micronutrient]
84425	Thiamine (Vitamin B-1) [micronutrient]
84446	Tocopherol alpha (Vitamin E) [micronutrient]
84590	Vitamin A [micronutrient]
84591	Vitamin, not otherwise specified [micronutrient]
84597	Vitamin K [micronutrient]
84630	Zinc [micronutrient]
90875	Individual psychophysiological therapy incorporating biofeedback training by any modality (face-to-face with the patient), with psychotherapy (e.g., insight oriented, behavior modifying or supportive psychotherapy); approximately 20-30 minutes
90876	approximately 45-50 minutes
90901	Biofeedback training by any modality
90912	Biofeedback training, perineal muscles, anorectal or urethral sphincter, including EMG and/or manometry, when performed; initial 15 minutes of one-on-one physician or other qualified health care professional contact with the patient
+90913	each additional 15 minutes of one-on-one physician or other qualified health care professional contact with the patient (List separately in addition to code for primary procedure)
96902	Microscopic examination of hairs plucked or clipped by the examiner (excluding hair collected by the patient) to determine telogen and anagen counts, or structural hair shaft abnormality
97014	Application of a modality to one or more areas; electrical stimulation (unattended)
97032	Application of a modality to one or more areas; electrical stimulation (manual), each 15 minutes
97039	Unlisted modality (specify type and time if constant attendance)
97110	Therapeutic procedures, one or more areas, each 15 minutes; therapeutic exercises to develop strength and endurance, range of motion and flexibility
97124	Therapeutic procedure, one or more areas, each 15 minutes; massage, including effleurage, petrissage and/or tapotement (stroking, compression, percussion)
97139	Unlisted therapeutic procedure (specify)
97140	Manual therapy techniques (e.g., mobilization/manipulation, manual lymphatic drainage, manual traction), one or more regions, each 15 minutes
97150	Therapeutic procedure(s), group (two or more individuals)
97530	Therapeutic activities, direct (one-on-one) patient contact (use of dynamic activities to improve functional performance), each 15 minutes
97799	Unlisted physical medicine/rehabilitation service or procedure
97810	Acupuncture, one or more needles, without electrical stimulation; initial 15 minutes of personal one-on-one contact with patient
+ 97811	without electrical stimulation, each additional 15 minutes of personal one-on-one contact with the patient, with re-insertion of needle(s) (List separately in addition to code for primary procedure)
97813	with electrical stimulation; initial 15 minutes of personal one-on-one contact with patient
+ 97814	with electrical stimulation, each additional 15 minutes of personal one-on-one contact with the patient, with re-insertion of needle(s) (List separately in addition to code for primary procedure)
98940	Chiropractic manipulative treatment (CMT); spinal, one to two regions
98941	spinal, three to four regions
98942	spinal, five regions
98943	extraspinal, one or more regions
HCPCS codes not covered for indications listed in the CPB:
No specific codes:
Intravenous micronutrient therapy (Myers' cocktail), Vitamin C infusion, Buteyko breathing technique, Salt room therapy, Vibro-acoustic therapy or Marijuana, Vibratory pads, Denneroll posture regainer, Gua Sha (scraping therapy), comprehensive muscular activity profiler (CMAPPro), weighted blanket, AmpCoil device, Emerg Auto-Emersion-Therapy mattress, Exosome therapy, glutathione infusion, intravenous curcumin infusion, pharmaco-puncture (herbal acupuncture)
B4172	Parenteral nutrition solution; amino acid, 5.5% through 7%, (500 ml = 1 unit) - homemix
G0176	Activity therapy, such as music, dance, art or play therapies not for recreation, related to the care and treatment of patient's disabling mental health problems per session (45 minutes or more)
J3420	Injection, vitamin B-12 cyanocobalamin, up to 1000 mcg [Cari Loder regimen]
J3475	Injection, magnesium sulfate, per 500 mg
J3570	Laetrile, amygdalin, vitamin B-17
M0075	Cellular therapy
M0300	IV chelation therapy (chemical endarterectomy)
P2031	Hair analysis (excluding arsenic)
S8940	Equestrian/hippotherapy, per session
S9451	Exercise classes, nonphysician provider, per session [pilates]
T2036	Therapeutic camping, overnight, waiver; each session [Wilderness Program]
T2037	Therapeutic camping, day, waiver; each session [Wilderness Program]
Other HCPCS codes related to the CPB:
A4595	Electrical stimulator supplies, 2 lead, per month (e.g., TENS, NMES)
E0720	Transcutaneous electrical nerve stimulation (TENS) device, two leads, localized stimulation
E0730	Transcutaneous electrical nerve stimulation (TENS) device, four or more leads, for multiple nerve stimulation
E0731	Form-fitting conductive garment for delivery of TENS or NMES (with conductive fibers separated from the patient's skin by layers of fabric)
E0746	Electromyography (EMG), biofeedback device
G0281	Electrical stimulation, (unattended), to one or more areas, for chronic stage III and stage IV pressure ulcers, arterial ulcers, diabetic ulcers, and venous stasis ulcers not demonstrating measurable signs of healing after 30 days of conventional care, as part of a therapy plan of care
G0282	Electrical stimulation, (unattended), to one or more areas, for wound care other than described in G0281
G0283	Electrical stimulation (unattended), to one or more areas for indication(s) other than wound care, as part of a therapy plan of care
J1815, J1817, S5550 - S5571	Insulin
ICD-10 codes not covered for indications listed in the CPB :
F32.0 - F32.9	Major depressive disorder, single episode
F33.0 - F33.9	Major depressive disorder, recurrent
F41.0 - F41.9	Other anxiety disorders
F41.0	Panic disorder [not covered for weighted blanket]
G89.4	Chronic pain syndrome
M79.7	Fibromyalgia
Numerous options	Soft tissue injuries [Not covered for comprehensive muscular activity profiler (CMAPPro)]
Glutathione infusion:
ICD-10 codes not covered for indications listed in the CPB :
D83.0 - D83.9	Common variable Immunodeficiency
G62.89	Other specified polyneuropathies [chemotherapy-induced neuropathy]
K59.1	Functional diarrhea
N14.1 - N14.2	Nephropathy induced by other or unspecified drugs, medicaments and biological substances [contrast media-induced nephropathy]
R53.82	Chronic fatigue, unspecified

The above policy is based on the following references: