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Cannabis and Pain: A Clinical Review

1 Division of Alcohol and Drug Abuse, McLean Hospital, Belmont, Massachusetts.

2 Harvard Medical School, Boston, Massachusetts.

Matthew D. Palastro

1 Division of Alcohol and Drug Abuse, McLean Hospital, Belmont, Massachusetts.

Brian Johnson

3 State University of New York Upstate Medical University, Syracuse, New York.

Joseph W. Ditre

4 Department of Psychology, Syracuse University, Syracuse, New York.

Abstract

Introduction: Cannabis has been used for medical purposes across the world for centuries. As states and countries implement medical and recreational cannabis policies, increasing numbers of people are using cannabis pharmacotherapy for pain. There is a theoretical rationale for cannabis’ efficacy for pain management, although the subjective pain relief from cannabis may not match objective measurements of analgesia. As more patients turn to cannabis for pain relief, there is a need for additional scientific evidence to evaluate this increase.

Materials and Methods: Research for this review was performed in the PubMed/National Library of Medicine database.

Discussion: Preclinical studies demonstrate a narrow therapeutic window for cannabis as pharmacotherapy for pain; the body of clinical evidence for this indication is not as extensive. A recent meta-analysis of clinical trials of cannabis and cannabinoids for pain found modest evidence supporting the use of cannabinoid pharmacotherapy for pain. Recent epidemiological studies have provided initial evidence for a possible reduction in opioid pharmacotherapy for pain as a result of increased implementation of medical cannabis regimens.

Conclusion: With increased use of medical cannabis as pharmacotherapy for pain comes a need for comprehensive risk-benefit discussions that take into account cannabis’ significant possible side effects. As cannabis use increases in the context of medical and recreational cannabis policies, additional research to support or refute the current evidence base is essential to attempt to answer the questions that so many healthcare professionals and patients are asking.

Introduction: Promising Compounds, Changing Landscape

Cannabis has been used around the world for centuries and the purpose for its use has varied throughout that time. 1 However, the utilization of cannabis for medicinal purposes has been consistent. Starting with the Chinese around 2900 B.C., many civilizations have transcribed their use of cannabis for a variety of conditions, from joint pain and muscle spasms to conditions such as gout and malaria. 1 While cannabis has been deployed medicinally for myriad medical conditions, the scientific rationale for its efficacy for these conditions is, in many cases, not clear. Four thousand years later, scientists are still trying to determine the exact medical conditions, if any, cannabis is effective in treating.

Research into cannabis and its uses has been hindered by a debate over its legality. 2 In 1976, the United States Controlled Substances Act classified cannabis as a Schedule I drug, meaning that it has a high potential for abuse and no accepted medical uses. However, as of March 2017, 28 states and the District of Columbia have enacted laws allowing the medical use of cannabis and 8 states, plus the District of Columbia, have legalized recreational use of cannabis. 3 The accepted conditions vary from state to state, in large part, due to the lack of randomized placebo-controlled studies researching the efficacy of cannabis for specific ailments. 4 Despite a paucity of standardized and controlled trial research to evaluate the short- and long-term health outcomes of cannabis use, all states are consistent in including chronic pain as one of the conditions for which cannabis is an approved pharmacotherapy. Indeed, pain relief is the most commonly cited reason for the medical use of cannabis. 4–6

Whether cannabis is the best treatment for pain or not, many patients around the world believe that cannabis has helped them with their pain. 7 As more and more states legalize cannabis for medicinal uses, a greater number of patients will ask their healthcare provider if it would be an effective treatment for their condition. Healthcare providers are in a difficult situation: there are only two cannabinoids currently approved by the United States Food and Drug Administration, and state regulations require them to recommend cannabis broadly, leaving the details about cannabis strains and dosing to be determined at the dispensaries. Interest in the use of cannabis for pain may be further catalyzed by a recent report put forth by the National Academies Committee on the Health Effects of Marijuana, 8 in which the authors concluded that there is “conclusive or substantial evidence” that cannabis is effective for the treatment of chronic pain in adults. Furthermore, even if physicians do not recommend cannabis for their own patients, they should at least be educated regarding the extensive effects of cannabis. Unfortunately, many patients currently use cannabis to treat a host of medical problems and do so without contacting their healthcare provider. 7 Healthcare professionals need to be prepared to answer questions regarding cannabis use and the potential effect it would have on each patient’s treatment.

Cannabis and pain: a brief history

The utilization of cannabis for pain can be traced back to ancient Chinese texts, dating to 2900 B.C. The Shennong Ben Cao Jing, a Chinese encyclopedia on agriculture and medicine, contains the oldest written record of cannabis as a medicine, recommending cannabis for constipation, rheumatic pain, female reproductive tract disorders, and malaria. 9 Furthermore, the plant was used in conjunction with wine to anesthetize patients during surgical procedures. 10 The Chinese mostly utilized cannabis seeds that contain very low levels of delta-9-tetrahydrocannabinol (Δ 9 THC), one of the main compounds in cannabis thought to have therapeutic effects. 10

Around 1000 year B.C., more parts of the cannabis plant started to be used medicinally in India. The female plant’s flowers were utilized and three different preparations of cannabis with varying degrees of potency were developed. 9 The strongest preparations were used as an analgesic, hypnotic, tranquilizer, antispasmodic, and anti-inflammatory agent. 11,12 It was not until the early 19th century that cannabis started to be explored in Western medicine. 13

Although the use of cannabis as a medicine in western cultures started off slowly, by the end of the 19th century, over 100 publications on medicinal cannabis were published in Europe and the United States. 14 Within that time, the medical indications for cannabis mostly focused on its hypnotic and analgesic effects. Since then, medical cannabis use has waxed and waned due to legal restrictions as well as the difficulty with replicating its effects between individuals. 11,15 Since the 1960s, both recreational cannabis use and medicinal cannabis use have increased rapidly in the United States. In 2015, an estimated 22.2 million Americans aged 12 or older were current users of cannabis, which corresponds to 8.3% of the U.S. population aged 12 or older. 16 Recently, research into cannabis expanded exponentially and the use of cannabis for pain became one of the most widely studied subtopics. 17

There are two ways to consider the rationale for cannabis pharmacotherapy for pain, conceptually and according to the evidence base. In this review, we will examine both.

Materials and Methods

Standard searches of the PubMed/National Library of Medicine database for the listed keywords and references from literature for pertinence to cannabis and the clinical management of pain were undertaken.

The subjective experience of pain

Pain has long been characterized as a subjective experience encompassing sensory-physiological, motivational-affective, and cognitive-evaluative components. 18 Approximately, 100 million U.S. adults are encumbered by chronic pain 19,20 ; pain motivates greater than 50% of all annual physician visits, 21 and recent estimates indicate a pain-related financial burden in excess of $600 billion in annual healthcare costs and lost productivity. 19 The three main pain systems are nociceptive, neuropathic, and central. 22 Nociceptive pain is caused by damage to body tissue and is usually described as sharp, aching, or throbbing pain. In response to tissue injury, invading immune cells secrete histamine, serotonin, bradykinin, prostaglandin, elevated levels of tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, and interleukin 17. 23 Signals of tissue injury are carried by fine C- and A-gamma peripheral nerves to dorsal root ganglia, up the spinothalamic track to the thalamus, and then on to the cortical area. 24 It is important to note that this is the only nociceptive system by which the survival value of pain to alert the organism to potential or occurring tissue damage exists. Nociceptive pain has warning and defensive properties. The other two pain systems, neuropathic and central, involve nonfunctional pain signals with disease involving the interpreting system. 25,26

Neuropathic pain is caused by damage to sensory or spinal nerves, which send inaccurate pain messages to higher centers. 26 For example, in diabetic neuropathy, the origin of foot pain is not in the tissue, but rather, the peripheral nerves. The disease attacks the peripheral nerves, resulting in an aberrant signal interpreted by the brain as pain in the feet. Centralized pain is the result of amplification of peripheral signals due to persistent central nervous system dysfunction. 22 Pain may be present despite a lack of a clear peripheral cause. A classic example is fibromyalgia. 25 The Clauw metaphor is that the electric guitar is a quiet instrument until the amplifier (brain) is plugged in. The central nervous system amplification makes the pain impossible to ignore.

The complex nature of pain can make it difficult to understand another’s pain. First, there are many genetic variants of pain, such as alleles of the SCN9A gene. SCN9A variants determine typical pain experiences, heightened pain, and rarely, the inability to feel pain by regulating the expression of voltage-gated sodium channel Na(v)1.7 mRNA, a resulting protein that is an important contributor to generation and conduction of action potentials of nociceptive neurons of dorsal root ganglia. 24 Low Na(v)1.7 results in low initiation and propagation of pain signals, and therefore high pain thresholds while high Na(v)1.7 would result in exaggerated pain sensitivity.

Second, the relationship of the observer to the pain experiencer is relevant to the observer’s ability to gauge the extent of the experiencer’s pain. When one feels close to another, one is more concerned with another’s pain, in part, because different brain areas are activated by empathic connection versus when considering the pain experience of a stranger. 27 For example, emergency physicians were thrice more likely to prescribe opioids to patients in motor vehicle accidents who had not completed high school than patients who shared their graduate level of education, suggesting that empathy and concern about prescribing a drug with addictive potential may affect the decision. 28

Finally, pain is an affect, or a subjective aspect of an emotion. However, an affect is a combination of innate endowment, childhood and adult history as metabolized through the consciousness of the person, and interpersonal relatedness. Pain experienced by a person with the normal SCN9A gene endowment might be dramatically different from pain caused by the same peripheral injury in someone with the high pain SCN9A gene variant suffering from serious psychiatric disorders such as major depressive disorder or borderline personality disorder. 29,30 These individuals’ responses to pain will likely be different.

Substances Used for Pain

Cannabis is rarely the first drug that a patient takes to mitigate pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit pain by addressing local tissue inflammation. They inhibit cyclooxygenase (COX), an enzyme required to make the vasodilator prostaglandin. Therefore, the painful swelling of peripheral tissues is decreased. NSAIDs can be used daily for prolonged periods to manage inflammatory conditions such as arthritis. 31

Alcohol also has an extensive history as a substance used in response to pain, and epidemiological data substantiate a high co-occurrence of pain and alcohol use. 32 For example, past-month pain is highly prevalent among individuals seeking treatment for alcohol use disorder (AUD; e.g., 73%), 33 and chronic pain patients are up to 60% more likely to endorse heavy drinking and/or meet diagnostic criteria for AUD, even after accounting for concurrent psychopathology and other substance use problems. 34–36 Although there is some evidence that drinking alcohol can confer short-term pain inhibition, such effects may require consumption at doses that exceed guidelines for moderate daily use, and the development of tolerance would likely require more alcohol to achieve the same degree of acute analgesia. 37 There is also converging evidence 38 that periods of abstinence following chronic alcohol consumption tend to be associated with increased sensitivity to pain, which in turn could promote relapse to drinking. Alcohol is mood-altering and addictive, thus physicians do not recommend that patients use alcohol to treat either acute or chronic pain.

Like alcohol, nicotine and tobacco smoking have long been implicated in the amelioration of pain. 39,40 Prevalence estimates indicate that individuals with chronic pain (vs. no chronic pain) are about twice as likely to be current smokers, with rates of smoking among treatment-seeking pain patients ranging from 49% to 68%. 41–44 Although a recent meta-analysis showed that nicotine can produce modest acute analgesia among humans, chronic cigarette smoking has been identified as a unique risk factor in the incidence and progression of several chronically painful conditions. 45,46 In terms of using nicotine for pain relief, the experience of pain has been shown to be a potent motivator of smoking behavior, 47 and pain patients have reliably endorsed smoking cigarettes to cope with pain. 48 Commensurate with evidence of complex interrelations between pain and tobacco smoking, research has also shown that daily smokers are nearly five times more likely to meet past-year diagnostic criteria for opioid abuse or dependence than never smokers. 49

The aberrant use of opioid medications is a growing public health crisis, and factors that have been shown to confer heightened risk for prescription opioid misuse include the presence of chronic pain and co-occurring substance use and mood disorders. 50–52 Opioid use accelerated in recent decades as a result of a social movement that cited cultural, societal, religious, and political attitudes as reasons for inadequate pain management. 53 The result of the widespread increase in opioid prescribing in the United States was quadrupling of opioid-caused deaths over 15 years. 54 One out of every 32 patients prescribed at least 200 morphine milligram equivalents per day died from chronic pain treatment. 55

As with other short-acting, consciousness-altering drugs, opioids are regarded by many patients as the best pharmacotherapy for pain relief. However, despite beliefs to the contrary, opioids are not optimal pharmacotherapy for chronic pain. Koob and LeMoal’s opponent process theory is one way to understand this phenomenon. 56 Every dose of opioids helps pain, the “a” process. Over time, drivers of dysphoria: pain, anxiety, and depression, the “b” process, overshoot the amelioration of pain ( Fig. 1 ) Consistent with opponent process theory and emerging research on pain and substance use, an evolving allostatic load conceptualization of pain and addiction posits that chronic substance use (along with commensurate repeated opponent process cycles of substance-induced analgesia and withdrawal-induced hyperalgesia) can dysregulate overlapping neural substrates and homeostatic pain mechanisms to engender a persistent imbalance that favors pain facilitation. 57

Opponent process theory.

Gradually, opioid-induced hyperalgesia is induced. This is a state where pain increases and generalizes due to central sensitization. In response to this pain, prescribed or illegally obtained doses of opioids are increased in an attempt to override the pain system.

Cannabis is now being considered in the same way that opioids were decades ago, the combination of a drug class that is experienced as pain-relieving medications in the context of a social movement supporting the treatment for pain. We now move to an examination of the mechanisms of cannabis effects on pain and the limited number of studies available that examine the outcomes of pain treatment with cannabis.

The endocannabinoid system and mechanisms of pain reduction

Neural and nonneural cells in injured tissues produce arachidonic acid derivatives called endocannabinoids. 58 They modulate neural conduction of pain signals by mitigating sensitization and inflammation through the activation of cannabinoid receptors that are also targeted by Δ 9 THC. 59 CB1 receptors modulate neurotransmitter release in the brain and spinal cord. 60 CB1 receptors are also present in nociceptive and nonnociceptive sensory neurons of the dorsal root ganglion and trigeminal ganglion, 61 as well as in defense cells such as macrophages, mast cells, and epidermal keratinocytes. 62 CB2 receptors are expressed at considerable levels in cells of hematopoietic origin. 63 Few CB2 receptors are located in the brain, spinal cord, and dorsal root ganglion, but they increase in response to peripheral nerve damage. 64 They regulate neuroimmune interactions and interfere with inflammatory hyperalgesia.

Endocannabinoids, anandamide, and 2-arachidonoyl-sn-glycerol (2-AG) are produced in injured tissues through distinct biochemical pathways to suppress sensitization and inflammation by activation of cannabinoid (CB) receptors. Anandamide can act as an autocrine or paracrine messenger and follows one of two pathways. In a reaction catalyzed by fatty acid amide hydrolase, it can be broken down to arachidonic acid and ethanolamine or, 65 alternatively, it can be directly transformed by COX-2 into proalgesic prostamides. 66 Anandamide mobilizes in response to inflammation and nerve injury and modulates nociceptive signals by activating local CB1 receptors. 2-AG is formed by the hydrolysis of phosphatidylinositol-4,5-biphosphate, a phospholipid at the center of a lipid pathway that produces numerous intracellular and transcellular messengers. 65 It plays a prominent role in the descending modulation of pain during acute stress. 67 Anandamide and 2-AG are recruited during tissue injury to provide a first response to nociceptive signals. Thus, understanding the function of endogenous cannabinoids helps explain the efficacy of exogenous cannabinoids, such as those found in the cannabis plant, in treating pain.

Therefore, the biologically hypothesized rationale for cannabinoid administration is whole-body exposure to exogenous cannabinoids to turn on pain inhibition. Of note, long-term studies of analgesia with exogenous cannabinoids would be necessary to adjudicate the question of whether pain could be continually suppressed in this manner, or whether the same hyperalgesic response to cannabinoids that is currently observed with opioids would ensue, another opponent process. Thus, physicians must be careful, just as with alcohol, nicotine, and opioids, about endorsing a drug where every use gives a subjective experience that pain is improved, and yet use of the drug over time has both hyperalgesic and potentially addictive properties.

Cannabis and pain studies

Results from studies evaluating cannabis pharmacotherapy for pain demonstrate the complex effects of cannabis-related analgesia. There are multiple randomized, controlled clinical trials that show cannabis as an effective pharmacotherapy for pain. 68 However, further examination of pre-clinical studies of cannabis in pain models underscores the nuances of cannabis’ analgesic effects. THC has been shown to produce analgesic and antihyperalgesic effects in animal models, 69,70 and experimental research examining the effects of cannabis on human pain responding has focused either on healthy adults or clinical pain samples. For example, Wallace et al. tested the effects of smoked cannabis (low, medium, or high doses vs. inactive placebo) on intradermal capsaicin-induced pain responses using a randomized, double-blind, crossover trial in 15 healthy volunteers (mean age of 28.9; 58% male). 71 Results indicated a significant decrease in pain with the medium cannabis dose and a significant increase in pain with the high dose. No differences were observed with the low cannabis dose, and there was no effect on the area of hyperalgesia at any dose. The authors concluded that there is likely a therapeutic window of modest analgesia for smoked cannabis.

Another experimental study with 18 healthy female volunteers tested the effects of orally administered cannabis extract (vs. active placebo) on sunburn and intradermal capsaicin pain responses using a double-blind, crossover trial. 72 Results indicated that the cannabis extract did not produce any analgesic or antihyperalgesic effects. There was also some evidence of an unexpected hyperalgesic state in the cannabis group. These authors concluded that the utility of cannabis use for acute pain relief is limited by the poorly understood therapeutic window and the dose-dependent occurrence of psychotropic side effects.

In terms of clinical pain, a recent systematic review and meta-analysis of cannabinoids for medical use that examined 28 randomized trials among 2454 patients with chronic pain indicated that, compared with placebo, cannabinoids were associated with greater a reduction in pain (37% vs. 31%; OR 1.41, 95% CI 0.99 to 2.00) and greater average reduction in numerical pain ratings (−0.46, 95% CI −0.80 to −0.11). 73 Whiting et al. concluded that there was moderate evidence to support the use of cannabinoids for the treatment of chronic pain. In this review, neuropathy was the most commonly cited source of chronic pain. The majority of studies focused on testing the effects of plant-derived cannabinoids. Only 5 of the 28 trials assessed the effects of vaporized or smoked cannabis plant flower. Of note, cannabinoids were associated with an increased risk for short-term adverse events, including serious adverse events, compared to placebo.

One recent study not included in Whiting’s meta-analysis was a placebo-controlled trial of inhaled aerosolized cannabis, which demonstrated a dose-dependent reduction in diabetic peripheral neuropathy spontaneous pain ratings among patients with treatment-refractory pain. 74 Finally, and most recently, Wilsey et al. conducted a randomized, placebo-controlled crossover trial utilizing vaporized cannabis among 42 participants with central neuropathic pain related to spinal cord injury and disease. 75 Results indicated that vaporized cannabis flower reduced neuropathic pain scale ratings, but there was no evidence of a dose-dependent effect. These authors concluded that additional research is needed to examine how interactions among cannabinoids may influence analgesic responding.

Collectively, this research indicates that although the results of experimental studies with healthy adults are mixed, there is converging evidence to support the notion that cannabis can produce acute pain-inhibitory effects among individuals with chronic pain. This observation is consistent with determinations made by authors of the recent National Academies report on cannabis that there is “conclusive or substantial evidence” of benefit from cannabis or cannabinoids for chronic pain. However, it is important to also highlight their statement that more research is needed to better understand the efficacy, dose–response effects, routes of administration, and side effect profiles for cannabis products that are commonly used in the United States. 8

Clinical issues

According to the DSM 5 heuristic, 76 a diagnosis of cannabis use disorder (CUD) requires a pattern of cannabis use leading to clinically significant impairment or distress characterized by the presence of two or more of 11 prototypical symptoms within a 12-month period. These symptoms can be organized into three broad categories: (1) physical symptoms including craving, withdrawal, and tolerance, (2) use-induced psychosocial problems, and (3) increased drug-use and/or drug-seeking behavior. It has been estimated that one out of every 10 people who ever use cannabis will develop a CUD, 77–79 and nationally representative U.S. data indicate that consequences consistent with CUD are endorsed by ∼30% of all current users. 80 The cannabis withdrawal syndrome typically results from abrupt cessation with a time course that may persist for ∼14 days following discontinuation (similar to tobacco withdrawal). 81–83 Importantly, both acute intoxication and withdrawal frequently produce symptoms that feature prominently among those with chronic pain (i.e., mood disturbance and sleep problems). 82

Consistent with previously published conceptualizations of interrelations between pain and substance use, 39,40,84 pain and cannabis use may be expected to interact in the manner of a positive feedback loop, resulting in greater pain and the development or maintenance of CUD. Negative affect would also be hypothesized to play a key mechanistic role, which is consistent with the identification of negative affect as a principal component in theoretical conceptualizations of pain processing and addiction motivation. 85,86 Over time, bidirectional relationships between pain and cannabis use may result in more severe functional impairment, greater pain-induced motivation to use cannabis, and increased negative affect and sensitivity to pain during periods of cannabis abstinence. Furthermore, expectations that abstaining from cannabis may exacerbate both pain and negative affect could serve as important barriers to cannabis cessation.

One important implication of this conceptualization is that individuals with chronic pain may develop unique CUD profiles that require specialized treatment. For example, chronic pain patients who engage in treatment for CUD may benefit from taking additional measures to manage their pain during the early stages of cannabis abstinence. Similarly, patients receiving pain treatment may benefit from interventions that aim to reduce the use of cannabis for pain-coping purposes. Finally, given that pain motivates more than half of all annual physician visits in the United States, 87 patients who present to primary care with co-occurring pain and cannabis use may benefit from an integrated treatment delivered within that setting. Additional research is needed to better understand the interplay of pain and cannabis use both over time and during the course of a cessation attempt. Clinicians may also consider the utility of sequential or integrated treatment for pain and CUD.

As cannabis is evaluated as pharmacotherapy and its use becomes more widespread, its significant side effects remain. Like other substances, there are potential adverse effects with acute and chronic use. Cognitive impairment can occur with both acute and chronic use, and adverse cognitive effects may be one area where the effects of chronic cannabis use could be worse than chronic opioid use. Although the acute effects of cannabis use, on driving for example, have received increasing attention with the implementation of medical and recreational cannabis policies, the effects of chronic use are better described. 88 Regular cannabis use, especially while the brain is under development, is associated with an increased risk of anxiety, depression, and psychotic illness, and cannabis can worsen the courses of these disorders. 68 These associations are especially important given the common co-occurrence of chronic pain and psychiatric conditions. 89 The implementation of medical and recreational cannabis policies offer an opportunity to collect longitudinal data on the effects of cannabis use. As we continue to collect such data, cannabis pharmacotherapy for pain management must be based upon thorough risk-benefit discussions.

Cannabis and Opioid Interactions

As more states introduce medical and recreational cannabis policies, we continue to learn more about the relationship between cannabis and opioids. Many patients have described a decreased need for prescription opioids after starting medical cannabis regimens. Many substances with addictive properties utilize common neural pathways, providing a theoretical basis for such anecdotes. Recently, rigorous studies have begun to provide evidence for these anecdotes as well. Bachhuber et al. described that states with medical cannabis laws had significantly lower annual opioid overdose mortality rates compared to states without medical cannabis. 90 This finding may be the result of patients with chronic pain initiating pharmacotherapy with medical cannabis, thereby lowering the need for opioid pharmacotherapy. Less reliance on opioid pharmacotherapy may in turn lead to fewer fatal opioid overdoses. A recent examination of Medicare claims data also showed that the use of prescription pain medications, including opioids, was significantly reduced in states following the implementation of medical cannabis laws. Finally, another study demonstrated that the percentage of drivers testing positive for opioids after traffic fatalities was significantly reduced in states with medical cannabis laws compared to states without such laws. 91 Taken together, these studies provide initial support for medical cannabis being correlated with decreased opioid-induced mortality. Further studies are necessary to further elucidate the role of cannabis as a potentially safer alternative to opioids for pharmacological pain management.

Conclusions

This is a pivotal time in the history of cannabis and cannabinoid research. In the context of increasing debates on the merits of medical and recreational cannabis policies, we need a corresponding increase in cannabis research. Many advocates on either side of these debates appear content to promote their agendas without placing priority on funding and supporting research that would answer key questions about the safety of cannabis and its potential medical indications. The often contentious debate about the efficacy of cannabis pharmacotherapy for pain is an important example. There is evidence, although limited, to support the use of cannabis pharmacotherapy in certain clinical scenarios. For example, if a patient with chronic pain and their healthcare provider work together through first- and second-line treatment modalities without success, a trial of cannabis or a cannabinoid may be a reasonable next step. As cannabis use increases, additional research to support or refute the current evidence base is essential to attempt to answer the questions that so many healthcare professionals and patients are asking.

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Medical Cannabis for the Treatment of Chronic Pain: A Review of Clinical Effectiveness and Guidelines

CADTH Rapid Response Report: Summary with Critical Appraisal

Srabani Banerjee and Suzanne McCormack .

Abbreviations

College of Family Physicians of Canada

Context and Policy Issues

Chronic pain is defined as pain that persists for more than three months. 1 It may present as headache, musculoskeletal pain, visceral pain, neuropathic pain, pain arising from rheumatic disease, and cancer pain. 1

Chronic pain is a global problem. 2 In Canada, approximately 25% adults have a chronic pain condition. 2 The prevalence estimates of chronic pain are likely to vary depending on the sample population surveyed, and the assessment method. 3 Costs associated with chronic pain include both direct and indirect costs. It is estimated that in Canada the annual direct cost to the healthcare system is over six billion dollars and the annual indirect cost due to job loss and sick days is over 37 billion dollars. 2 Chronic pain is a problem for the individual suffering, and also a societal burden.

Therapies for management for chronic pain include several pharmacological agents (such as tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and opioid analgesics). 4 , 5 However, these medications offer limited pain relief and are associated with adverse effects. 4 , 5 There is increasing interest in the use of cannabis-based medicines. Cannabis-based medicines contain cannabinoids derived from the cannabis plant, including delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), or a combination of THC and CBD 6 . There is, however, uncertainty and controversy regarding the use of cannabis-based medicines for the management of chronic pain. 7

The purpose of this report is to review the clinical effectiveness of medical cannabis for the treatment of chronic pain. Additionally, this report aims to review the evidence-based guidelines regarding associated with the use of medical cannabis for the treatment of chronic pain.

Research Questions

Key Findings

Based on four overviews (with overlapping systematic reviews), and one systematic review of guidelines, 8 there is some suggestion of benefit with cannabis-based medicines for neuropathic pain. However, benefits need to be weighed against harms. Findings are inconsistent for effect of cannabis-based medicines in patients with fibromyalgia, musculoskeletal pain, Crohn’s disease, and multiple sclerosis.

Six evidence-based guidelines were identified. The majority of the guidelines present recommendations for chronic neuropathic pain. The guidelines report that cannabis-based medicines may be considered as a treatment option for patients with neuropathic pain, with chronic non-cancer pain, and with chronic non-cancer, non-neuropathic pain, but with some caveats. Recommendations are against the use of cannabis-based medicines for pain associated with fibromyalgia and back pain in two guidelines and for pain associated with headache, rheumatoid arthritis and osteoarthritis in one guideline. For pain management in multiple sclerosis patients, one guideline mentions that cannabis-based medicines may or may not be offered, depending on the type cannabis-based medicine and patient condition.

Findings need to be interpreted considering the limitations (such studies of variable quality [low to moderate], and studies of short duration)

Methods

Literature Search Methods

A limited literature search was conducted by an information specialist on key resources including Medline, the Cochrane Library, the University of York Centre for Reviews and Dissemination (CRD) databases, the websites of Canadian and major international health technology agencies, as well as a focused Internet search. The search strategy was comprised of both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were Medical Marijuana and chronic pain. No filters were applied to limit the retrieval by study type. The search was also limited to English language documents published between January 1, 2014 and June 24, 2019.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Table 1

Exclusion Criteria

Studies were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, or were published prior to 2014. Studies on acute pain or cancer pain were excluded. Guidelines with unclear methods were excluded.

Critical Appraisal of Individual Studies

The included overviews (systematic reviews of systematic reviews) were critically appraised by one reviewer using AMSTAR 2, 9 and evidence-based guidelines were critically assessed using AGREE 2. 10 Summary scores were not calculated for the included studies, rather, the strengths and limitations of each individual study were described narratively.

Summary of Evidence

Quantity of Research Available

A total of 644 citations were identified in the literature search. Following screening of titles and abstracts, 594 citations were excluded and 50 potentially relevant reports from the electronic search were retrieved for full-text review. Two potentially relevant publications were retrieved from the grey literature search for full text review. Of these potentially relevant articles, 41 publications were excluded for various reasons, and 11 publications met the inclusion criteria and were included in this report. These comprised four overviews (systematic review of systematic reviews), 11 – 14 one systematic review of guidelines, 8 and six guidelines. 7 , 15 – 19 Appendix 1 presents the PRISMA 20 flowchart of the study selection.

Additional references of potential interest are provided in Appendix 6.

Summary of Study Characteristics

Characteristics of the overviews, systematic review of guidelines, and guidelines are summarized and additional details are provided in Appendix 2, Table 2 and Table 3

Study Design

Four relevant overviews 11 – 14 identified were published between 2017 and 2018. One overview 11 included 23 relevant systematic reviews published between 2007 and 2017. The second overview included 10 systematic reviews published between 2009 and 2016. The third overview included 11 systematic reviews published between 2003 and2016. The last overview included 11 systematic reviews published between 2013 and 2016. There was overlap in the systematic reviews included in the overviews (Appendix 5).

One systematic review 8 of guidelines and six guidelines 7 , 15 – 19 were selected. The systematic review 8 of guidelines was published in 2016 and included three relevant guidelines published between 2007 and 2010. The six guidelines 7 , 15 – 19 were published between 2014 and 2018. In three guidelines, 15 , 17 , 18 the recommendations were graded and in three guidelines 7 , 16 , 19 the recommendations were not graded.

Country of Origin

Countries indicated for the first authors of the overviews were Canada, 11 Australia, 14 and Germany. 12 , 13

The country indicated for the systematic review 8 of guidelines was China. Countries indicated for the first author of the guideline document, or the guideline development groups were Canada, 15 , 16 , 18 US, 17 Australia, 19 and Germany. 7

Population

The populations assessed were patients with chronic pain, neuropathic pain, rheumatologic pain, fibromyalgia, and myasthenia gravis (MS) in one overview, 11 patients with chronic pain in the second overview, 12 patients with MS in the third overview, 14 and patients requiring pain management or palliative care in the last overview. 13

The systematic review 8 of guidelines assessed patients with neuropathic pain. Of the six guidelines, 7 , 15 – 19 one guideline, 15 was on patients who were refractory to standard medical therapy; the second guideline, 7 was on patients with chronic pain; the third guideline, 19 was on patients with chronic non-cancer pain; the fourth guideline, 18 was on patients with chronic pain or anxiety; the fifth guideline, 16 was on patients with chronic neuropathic pain; and the last guideline. 17 was on patients with MS. The guidelines were intended for health care providers involved with pain management.

Interventions and Comparators

In the overviews 11 – 14 the interventions were various types of cannabis-based medicines and comparators were placebo; in two overviews 12 , 13 an active comparator (amitriptyline) was also mentioned and in one overview 14 other treatments were compared but specifics were not reported.

The systematic review 8 of guidelines reviewed guidelines which reported on cannabinoids and also other pharmacologic agents (such as anticonvulsants, topical treatments, and opioids). Four guidelines 7 , 15 , 18 , 19 considered cannabis-based medicines and one guideline 16 considered complimentary and alternative medicines, which included as well cannabis-based medicine; and one guideline 17 included several pharmacological agents including as well cannabis-based medicines.

Outcome

Outcomes considered in the overviews included pain reduction, 11 – 14 quality of life, 14 tolerability, 13 withdrawal, 11 adverse events, 11 – 14 and serious adverse events. 11 , 13

The systematic review 8 of guidelines and all six guidelines 7 , 15 – 19 presented recommendations on pain management. Details regarding levels and grades of recommendations are presented in Appendix 2, Table 3.

Summary of Critical Appraisal

Critical appraisal of the included overviews, systematic review of guidelines, and guidelines are summarized below, and details for the overviews and systematic review of guidelines are presented in Appendix 3, Table 4; and details for the guidelines are presented in Appendix 3, Table 5 and Table 6.

The four overviews 11 – 14 were generally well conducted. In all four overviews, the objective was stated; a comprehensive literature was conducted; study selection was described; a list of included systematic reviews was presented, data extraction was done in duplicate, quality assessment was conducted, and the quality of the included systematic reviews were found to be variable. Article selection and quality assessment were done in duplicate in three overviews 11 , 12 , 14 and was unclear in one overview, 13 Publication bias was investigated in one overview 11 using a Funnel plot, but as both cancer (which is out of scope of this review) and non-cancer pain studies were included in the same plot it was unclear if there was any publication bias with respect to studies on non-cancer pain. In the remaining three overviews 12 – 14 publication bias was not investigated. In two overviews 11 , 13 it was mentioned that there were no conflicts of interest, and in two overviews 12 , 14 conflicts of interest were declared; some of the authors had association with pharmaceutical companies and it was unclear if there was any associated risk of bias with respect to the conduct of the overviews.

The systematic review 8 of the guidelines was generally well conducted. The objective was stated; a comprehensive literature was conducted; study selection was described; a list of included systematic reviews was presented, article selection was done by two reviewers, quality assessment was conducted, and the quality of the included guidelines were found to be variable. It was unclear if data extraction and quality assessment were done in duplicate; publication bias was not investigated The authors mentioned that there were no conflicts of interest.

In all six guidelines, 7 , 15 – 19 , the scope and purpose were mentioned or apparent, the guideline development group comprised experts in the area, and the target users were mentioned. Patient preferences were considered in one guideline, 15 and not in the remaining five guidelines. 7 , 16 – 19 In four guidelines 15 – 17 , 19 systematic methods were used to search for evidence, and in two guidelines 7 , 18 systematic methods appeared to have been used but details were lacking. The strengths and limitations of the evidence was mentioned in four guidelines, 15 , 17 – 19 and were not stated in two guidelines 7 , 16 The method of formulating the recommendation was mentioned in four guidelines 7 , 15 , 16 , 18 and was not stated in two guidelines. 17 , 19 Health benefits and harms were considered in five guidelines, 7 , 15 – 17 , 19 and was unclear in one guideline. 18 Four guidelines 7 , 15 – 17 were externally reviewed, and in two guidelines it was unclear. 18 , 19 In three guidelines 15 , 17 , 18 it was mentioned that there were no conflicts of interest, in two guidelines 7 , 16 conflicts of interest were declared but procedure to address the issue was not presented, and for one guideline 19 conflicts of interest were not presented.

Summary of Findings

Relevant study findings are summarized and a table of the main study findings and authors’ conclusions are presented in Appendix 4, Table 7 and Table 8.

Clinical Effectiveness of cannabis-based medicines

Four overviews, 11 – 14 were identified regarding the use of cannabis-based medicines for patients with non-cancer pain. Relevant findings are summarized, and a table of the main study findings and authors’ conclusions are presented in Appendix 4, Table 7.

In the overviews, cannabis-based medicines were mostly compared with placebo. The findings reported below for cannabis-based medicines are with respect to placebo.

One overview 11 reported that there was uncertainty with regard use of cannabinoids for pain management. It reported that there appeared to be some benefit with cannabinoids for neuropathic pain, but adverse effects were common, and benefits need to be weighed against harms.

The second overview 12 reported that findings were inconsistent for the use of cannabis-based medicines for the management of chronic pain; there appeared to be some benefit with respect to chronic neuropathic pain, and the evidence was insufficient with respect to pain associated with rheumatic diseases and fibromyalgia, precluding any definitive conclusions.

The third overview 13 reported that for chronic neuropathic pain there was some reduction in pain with cannabinoids, however there was limited evidence available. The authors reported that there was inadequate evidence to support treatment with cannabinoids in patients with fibromyalgia, Crohn’s disease, musculoskeletal pain, and rheumatoid arthritis. Cannabinoid use in pain management may cause adverse effects related to the central nervous system and psychiatric adverse events.

The fourth overview, 14 based on mostly low-quality evidence, reported that cannabis-based medicines had a positive effect or mixed effect with respect to pain management in MS patients, and the effect sizes were generally small. Effects of cannabis-based medicines on quality of life were mixed. Adverse effects with cannabis-based medicines were generally mild to moderate.

In summary, there is some suggestion of benefit with cannabis-based medicines for neuropathic pain. However, benefits need to be weighed against harms. Findings are inconsistent for the effect of cannabis-based medicines in patients with rheumatic disease, fibromyalgia, musculoskeletal pain, Crohn’s disease, and MS.

Guidelines

One systematic review 8 of guidelines and six guidelines 7 , 15 – 19 were selected. Relevant recommendations are summarized and related details are presented in Appendix 4, Table 8.

Chronic non-cancer pain

The guideline 19 of the Australian government mentions that cannabinoids should not replace current approved first-line treatments for chronic non-cancer pain.

Chronic non-neuropathic non-cancer pain

The guideline by Hauser et al. 7 mentions that in exceptional cases after careful assessment, cannabis-based medicines can be considered if all established treatments have failed,

Neuropathic pain

One systematic review 8 of guidelines and four guidelines 7 , 15 , 16 , 18 presented recommendations on neuropathic pain. The systematic review of guidelines by Deng et al. 8 recommends the use of cannabinoids as fourth-line treatment of neuropathic pain. The guideline by Hauser et al. 7 mentions that cannabis-based medicines can be considered as third-line therapy for chronic neuropathic pain. The guideline by Allan et al. 15 recommends against the use of medical cannabinoids for first- and second-line therapy for neuropathic pain (strong recommendation). It also mentions that under certain circumstances, medical cannabis could be considered for patients with refractory neuropathic pain (weak recommendation). The College of Family Physicians of Canada (CFPC) guideline 18 mentions that, before authorizing dried cannabis for treating neuropathic pain the physician should first adequately try other pharmacologic and non-pharmacologic therapies, followed by pharmaceutical cannabinoids. The guideline by Moulin et al. 16 recommends cannabinoids for the management of neuropathic pain but cautions that judicious prescribing practices are required.

Pain associated with other conditions

The guideline by Allan et al. 15 recommends against the use of medical cannabinoids for headache and pain due to rheumatologic conditions (including fibromyalgia, osteoarthritis, rheumatoid arthritis, and back pain) (strong recommendation). The guideline by CFPC 18 does not support the authorization of dried cannabis for treatment of pain conditions commonly seen in primary care, such as fibromyalgia or low back pain (Level III). The guideline by Yadav et al. 17 mentions that for reduction of patient-reported symptoms of spasticity and pain (excluding central neuropathic pain) in patients with MS, the clinicians may offer oral cannabis extract (Level A), and THC (Level B), It also mentions that for reduction of patient-reported symptoms of spasticity, pain or urinary frequency in patients with MS, the clinicians may offer Savitex, oromucosal cannabinoid spray (Level B). There is insufficient evidence to support or refute the use of smoked cannabis for the management of spasticity, pain, balance/posture, and cognition in MS patients (Level U).

In summary, majority of the guidelines present recommendations for chronic neuropathic pain. 7 , 15 , 16 , 18 It is reported that cannabis-based medicines may be considered as a treatment option for patients with neuropathic pain, but with some caveats. It is also mentioned that cannabis-based medicines may be considered for patients with chronic non-cancer pain, 19 and for patients with chronic non-cancer, non-neuropathic pain, 7 but with some caveats. Three guidelines 15 , 17 , 18 mention pain associated with other conditions (such as fibromyalgia, rheumatologic disease, headache, and MS); recommendations were inconsistent. Recommendations are against the use of cannabis-based medicines for pain associated with fibromyalgia and back pain in two guidelines 15 , 18 and for pain associated with headache, rheumatoid arthritis, and osteoarthritis in one guideline. 15 For pain management in MS patients, one guideline 17 mentions that cannabis-based medicines may or may not be offered, depending on the type cannabis-based medicine and patient condition.

Limitations

This report has several imitations. This report is intended as an overall summary of the efficacy and safety of cannabis treatment for chronic pain associated with a variety of disease conditions. Considering the many types of cannabis-based medicines studied, and many conditions associated with chronic pain, an exhaustive evaluation of specific cannabis-based medicines for specific pain conditions were beyond the scope of this report.

Though there were several systematic reviews included in the selected overviews, it should be noted that there was some overlap in the included systematic reviews (Appendix 5, Table 9). The overviews were well conducted but the evidence on which the findings were based were of variable quality (low to moderate quality) or insufficient, hence definitive conclusions are not possible. Sometimes results include both cancer and non-cancer pain. Though there were fewer studies on cancer pain compared to non-cancer pain, their impact on the results was uncertain. There was limited amount of evidence regarding the comparison of cannabis-based medicines with an active comparator. The studies were generally of short term varying between 4 days to 14 weeks (when reported) and long-term effects are not known. Findings should be interpreted with caution considering the limitations mentioned.

Conclusions and Implications for Decision or Policy Making

Four overviews (systematic review of systematic reviews), 11 – 14 one systematic review of guidelines, 8 and six evidence-based guidelines. 7 , 15 – 19 were identified

Based on four overviews 11 – 14 (with overlapping systematic reviews), one systematic review of guidelines, 8 there is some suggestion of benefit with cannabis-based medicines for neuropathic pain. However, benefits need to be weighed against harms. Findings are inconsistent for effect of cannabis-based medicines in patients with fibromyalgia, musculoskeletal pain, Crohn’s disease, and MS.

The majority of the guidelines present recommendations for chronic neuropathic pain. 7 , 15 , 16 , 18 The guidelines report that cannabis-based medicines may be considered as a treatment option for patients with neuropathic pain, 7 , 15 , 16 , 18 with chronic non-cancer pain, 19 and with chronic non-cancer, non-neuropathic pain, 7 but with some caveats. Recommendations are against the use of cannabis-based medicines for pain associated with fibromyalgia and back pain in two guidelines 15 , 18 and for pain associated with headache, rheumatoid arthritis and osteoarthritis in one guideline 15 For pain management in MS patients, one guideline 17 mentions that cannabis-based medicines may or may not be offered, depending on the type cannabis-based medicine and patient condition. Findings need to be interpreted considering the limitations mentioned.

Potential of adverse events associated with cannabis-based medicines need to be considered. Specific populations of patients may be more vulnerable to adverse effects of cannabis-based medications. High quality studies of longer duration are needed to determine definitively the clinical effectiveness and safety of cannabis-based medicines.

References

Appendix 1. Selection of Included Studies

Appendix 2. Characteristics of Included Publications

Table 2 Characteristics of Included Overviews (systematic review of systematic reviews)

Allan, 11 2018, Canada

Overview (systematic review of systematic reviews) on the use of medical cannabinoids. The overview included 23 relevant systematic reviews, published between 2007 and 2017. Numbers of RCTs included in the SRs varied between 2 and 28, and the numbers of patients in the SRs varied between 44 and 2454

Exclusion criteria: SRs not focused on medical cannabinoids, SRs focused on conditions besides pain, spasticity, or nausea and vomiting, SRs of observational studies, SRs in which >50% of the RCTs involved pediatric patients, SRs including <2 RCTs were excluded.

This overview had a broad focus and included SRs on acute pain, and cancer related pain. 31 SRs (published between 2001 and 2017) of which 23 reporting on pain and/or adverse events are discussed here.

Objective: To assess the effects of medical cannabinoids on pain, spasticity, and nausea and vomiting; and adverse events.

Patients with chronic pain, neuropathic pain, rheumatologic pain, fibromyalgia, and MS

Pain, adverse events

Study duration: NR

Hauser, 12 2018, Germany

Overview on the use of cannabis-based medicines. This overview was a qualitative SR of RCTs. This overview included 10 SRs, published between 2009 and 2016. Country of origin of the systematic reviews were not reported.

Exclusion criteria: Qualitative systematic reviews which did not explicitly mention the reasons for not performing meta-analysis were excluded.

Objective: To summarize the efficacy, tolerability, and safety of the use of cannabis medicine-based for treating chronic pain (non-cancer and cancer pain)

Patients with chronic pain (non-cancer and cancer pain).

Age: Any age (specific ages of patients in the SRs were not reported)

Interventions: medical cannabis; plant-derived cannabinoids (THC, THC/CBD); synthetic cannabinoid analogues nabilone); or synthetic drugs which manipulate the endocannabinoid system

Comparator: placebo (mostly) or active comparator (amitriptyline)

Change in pain status, tolerability (withdrawals due to adverse events), and safety (frequency of serious adverse events)

Study duration for RCTs included in the SRs: 4 hours to 14 weeks

Nielsen, 14 2018, Australia

Overview on the use of cannabis-based medicines. This overview included 11 SRs, published between 2003 and 2016. Country of origin of the systematic reviews were not reported.

Exclusion criteria: SRs that did not meet the minimum criteria (i.e. GRADE criteria: comprehensive literature search was conducted and characteristics of the included studies were presented) were excluded

Objective: To evaluate the therapeutic potential of cannabinoids for treating MS symptoms

Patients with MS

Age: not reported

Interventions: Cannabis Savita, Dronabinol, THC extract, Nabiximols, THC:CBD extracts, Nabilone, CBD extract.

Comparator: Placebo (mostly) or active comparator (not specified)

Pain, quality of life, adverse events

Other outcomes not relevant for this current report: spasticity; bladder function; ataxis and tremor; and sleep.

Study duration of included studies in the included SRs: 3 to 14 weeks

Hauser, 13 2017, Germany

Overview on the use of cannabis-based medicines. This overview included 11 SRs, published between 2013 and 2016. It also included 3 long-term, prospective observational studies (> 6 months duration) published in 2015, or 2016. Country of origin of the systematic reviews were not reported.

Exclusion criteria: Systematic reviews which did not include quantitative analysis and which did not explicitly mention the reasons for not performing meta-analysis were excluded.

Objective: To assess the efficacy and risks associated with use of cannabinoids for pain management and palliative care, based on systematic reviews of RCTs and to review prospective observational studies to assess long-term risks

Patients requiring pain management or palliative care.

Age: not reported

Interventions: medical marijuana, Nabilone, THC/CBD, and Dronabinol.

Comparator: Placebo or active comparator (amitriptyline)

Pain, adverse events

(Other outcomes not relevant for this report included: dyspnea, loss of appetite.)

Study duration: ranged between for the included systematic reviews 5 hours to 14 weeksranged between 6 weeks and 52 weeks in the 3 observational studies

Included 3 CPGs relevant for the current report. The CPGs were published between 2007 and 2010. One CPG was from NICE (UK), the second CPG was from IASP (international), and the third CPG was from Latin America.

Intended users of the CPGs: physicians involved in the management of neuropathic pain.

Exclusion criteria: consensus statements based on expert opinion, and documents focused entirely on a single unique condition were excluded

(This systematic review had a broad objective [management of neuropathic pain] and included 16 CPGs published between 2004 and 2014. Of these 16 CPGs, 3 CPGs reported on cannabinoids and are relevant for this current report. The remaining 13 CPGs did not report on cannabinoids, hence are not discussed here)

Patients with neuropathic pain

Interventions: Cannabinoids and other pharmacologic agents (such as anticonvulsants, topical treatments, SNRIs, opioids, sodium channel blockers)

Follow-up: Not applicable

CBD = cannabidiol; CPG = Clinical Practice Guideline; IASP = International Association for the Study of Pain; NICE = National Institute of Health and Care Excellence; NR = not reported; SNRIs = selective serotonin/noradrenaline reuptake inhibitors; SRs = systematic reviews; THC = delota-9-tetrahydrocannabinol

Table 3 Characteristics of Included Guidelines

Intended users: primary care providers.

Target population: not specified, appears to be for patients whose conditions are refractory to standard medical therapy

Pain, nausea and vomiting, spasticity, and adverse events

The method used for the development of the guideline was based on the Institute of Medicine’s outline for Clinical Practice Guidelines We Can Trust 21 and the GRADE methodology. 22

A systematic review of systematic reviews of RCTs was conducted

Recommendations were classified as strong or weak according to the GRADE methodology. 22

Recommendations were based on consensus.

GDG comprised 2 generalist family physicians, 2 pain-management focused family physicians, 1 inner-city family physician, 1 neurologist, 1 oncologist, 1 nurse practitioner, 1 pharmacist, and 1 patient representative

Recommendations were graded

Externally reviewed (by clinicians and patients)

Intended user: specialist and nonspecialist prescribers

Target population: Patients with chronic pain

Pain, adverse events

The method used for the development of the position paper was based on the recommendations of a clinical consensus statement development manual by Rosenfeld et al. 23

A selective literature search was conducted. In addition, systematic reviews and guidelines not identified in the search was provided by members of the task force.

Evidence was not graded

Recommendations were based on consensus and finally approved by all members of the task force after two Delphi procedures

Members of the task were comprised individuals with clinical and scientific experience.

Recommendations were not graded

Intended user: Doctors who prescribe medicinal cannabis and their patients

Medicinal cannabis use for CNCP (in palliative care, epilepsy, CINV, MS and chronic pain

Pain intensity, physical functioning, emotional functioning, patient global impression of change, withdrawals from the study, and adverse events

The method used for the development of the guideline was based on the GRADE system. 24

A systematic review of previously published systematic reviews was conducted based on PRISMA

The GRADE system 24 was used.

Recommendations were made by the Chronic Pain Working Group.

Also a workshop was held to review the available evidence and included representatives from consumer groups, medical colleges, special societies, and states and territories

Method used to formulate the recommendations were not specified.

Recommendations were not grade

Intended users: Not specifically stated but appears to be for prescribers of dried cannabis

Target population: Appears to be for patients with chronic pain or anxiety

Chronic pain or anxiety

Cannabis effectiveness, safety, and adverse effects

Literature search was conducted and evidence was reviewed. No details were presented.

Recommendations were classified as Level I (if based on well-conducted controlled trials or meta-analyses), Level II (if based on well-conducted observational studies), Level III (if based on expert opinion)

Recommendations were formulated based on consensus.

GDG comprised members of the Addiction Medicine and Chronic Pain Program Committees of the SIFP of the CFPC as well as other SIFP program committee members

Recommendations were graded.

Intended users: physiciuans, nurse practitioner, , and other allied health care individuals involved in the management of neuropathic pain.

Target population: not explicitly specified but appears to be individuals with chronic neuropathic pain

Pharmacologic management of chronic neuropathic pain (includes cannabis and other agents)

Efficacy and safety (details not presented)

A systematic literature search was conducted (to identify systematic reviews, meta-analyses, and treatment recommendations, guidelines and/or consensus statements) and evidence was reviewed

First line: “if there was high-quality evidence of efficacy (at least one class I study or two consistent class II studies – level of recommendation grade B or better)

[…]; positive results in at least two NeP models

[….], and if they were considered to be straight-forward and of sufficient tolerability to prescribe and monitor” (p329)

Second or third line: “if there was high-quality evidence, but the medication required more specialized follow-up and monitoring” (p329)

Fourth line: if there was at least one positive RCT, but further study was required

Recommendations were formulated based on consensus.

GDG comprised individuals with research and clinical expertise relevant to the pathophysiology and management of neuropathic pain.

Recommendations were not graded. However, they were classified as first-line, second-line, third-line or fourth-line.

Externally reviewed – published in peer-reviewed journal

Intended users: Appears to be for health care professional involved in the care of MS patients

Target population: Patients with MS

Cannabinoids and other complimentary, and alternative medicines (such as ginkgo biloba, Chinese medicine, glucosamine sulphate, massage therapy, mindfulness training, yoga)

Pain and other outcomes (such as spasticity, bladder symptoms, depression, anxiety, sleep, fatigue, cognitive function, tremor, paresthesia, and QoL)

The method used for the development of the guideline was not presented in detail however according to the ANN CPG process manual rigorous methods are followed.

A systematic review was conducted

Details were not presented however according to the AAN CPG process manual 25 rigorous methods are followed.

According to the manual: levels of recommendation were A, B, C and U.

“Level A rating requires at least two consistent Class I studies” (p.49) a

Level B rating requires at least one Class I study or two consistent Class II studies” (p.49) a

“Level C rating requires at least one Class II study or two consistent Class III studies” (p.49) a

Level U is based on insufficient evidence or Class IV studies (i.e., not meeting criteria for Class I to Class III) (p.49) a

Details were not presented however according to the AAN CPG process manual 25 rigorous methods are followed.

GDG comprised experts in the area.

Recommendations were graded

Externally reviewed – published in a peer-reviewed journal

CINV = chemotherapy induced nausea and vomiting; CFPC = College of Family Physicians of Canada; CNCP = chronic non-cancer pain; GDG = Guideline Development Group; GRADE = Grading of Recommendations, Assessment, Development, and Evaluation; MS = multiple sclerosis; NeP = neuropathic pain;PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-analyses; RCT = randomized controlled trial; SIFP = Section of Family Physicians with Special Interests or Focused Practices

Study class: “Class I: Prospective, randomized, controlled clinical trial with masked outcome assessment, in a representative population. The following are required: a) primary outcome(s) clearly defined b) exclusion/inclusion criteria clearly defined c) adequate accounting for drop-outs and cross-overs with numbers sufficiently low to have minimal potential for bias d) relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class II: Prospective matched group cohort study in a representative population with masked outcome assessment that meets a-d above OR a RCT in a representative population that lacks one criteria a-d.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement

Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion.” (p49 of ANN CPG process manual 25 )