Research ArticleResearch

Efficacy and adverse effects of medical marijuana for chronic noncancer pain

Systematic review of randomized controlled trials

Amol Deshpande, Angela Mailis-Gagnon, Nivan Zoheiry and Shehnaz Fatima Lakha
Canadian Family Physician August 2015, 61 (8) e372-e381;

Abstract

Objective To determine if medical marijuana provides pain relief for patients with chronic noncancer pain (CNCP) and to determine the therapeutic dose, adverse effects, and specific indications.

Data sources In April 2014, MEDLINE and EMBASE searches were conducted using the terms chronic noncancer pain, smoked marijuana or cannabinoids, placebo and pain relief, or side effects or adverse events.

Study selection An article was selected for inclusion if it evaluated the effect of smoked or vaporized cannabinoids (nonsynthetic) for CNCP; it was designed as a controlled study involving a comparison group, either concurrently or historically; and it was published in English in a peer-review journal. Outcome data on pain, function, dose, and adverse effects were collected, if available. All articles that were only available in abstract form were excluded.

Synthesis A total of 6 randomized controlled trials (N = 226 patients) were included in this review; 5 of them assessed the use of medical marijuana in neuropathic pain as an adjunct to other concomitant analgesics including opioids and anticonvulsants. The 5 trials were considered to be of high quality; however, all of them had challenges with masking. Data could not be pooled owing to heterogeneity in delta-9-tetrahydrocannabinol potency by dried weight, differing frequency and duration of treatment, and variability in assessing outcomes. All experimental sessions in the studies were of short duration (maximum of 5 days) and reported statistically significant pain relief with nonserious side effects.

Conclusion There is evidence for the use of low-dose medical marijuana in refractory neuropathic pain in conjunction with traditional analgesics. However, trials were limited by short duration, variability in dosing and strength of delta-9-tetrahydrocannabinol, and lack of functional outcomes. Although well tolerated in the short term, the long-term effects of psychoactive and neurocognitive effects of medical marijuana remain unknown. Generalizing the use of medical marijuana to all CNCP conditions does not appear to be supported by existing evidence. Clinicians should exercise caution when prescribing medical marijuana for patients, especially in those with nonneuropathic CNCP.

Few therapeutic options for chronic noncancer pain (CNCP) provide consistently successful outcomes; many fail to provide clinically meaningful reduction in pain, defined as a decrease in pain scores by at least 30%.1 Even with the widespread use of opioids, improvements in outcomes such as function and mood remain limited.2

Cannabis has had a long history of use for spiritual and religious purposes, as well as for various medical conditions.3 In 1999, an Institute of Medicine report4 supported the use of marijuana in medicine; however, the debate about the usefulness and safety of marijuana remains unresolved.

In Canada, the federal government brought forward the Marihuana for Medical Purposes Regulation in March 2014, replacing the previous Marihuana Medical Access Regulations (MMAR).5 In response to physicians’ concerns, most of the regulatory medical colleges in Canada have published recommendations for prescribing medical marijuana. Most colleges acknowledge the fact that proper studies have not yet been conducted, and one college in the province of Quebec restricts the use of medical marijuana to the context of a research framework.6

The primary objective of this systematic review was to determine whether smoked or vaporized cannabis provides pain relief in the CNCP population. Secondary objectives included determining its effect on function, identifying therapeutic doses, and documenting commonly associated adverse effects.

DATA SOURCES

Literature search

In April 2014, we identified eligible studies through an electronic search of MEDLINE, EMBASE, and the International Pharmaceutical Abstracts. The search strategy encompassed a theme that included the following terms: chronic noncancer pain, smoked marijuana or cannabinoids, placebo and pain relief, or side effects or adverse events.

Study selection

We selected an article for inclusion if it evaluated the effect of smoked or vaporized cannabinoids (nonsynthetic) for CNCP; it was designed as a controlled study involving a comparison group, either concurrently or historically; and it was published in English in a peer-reviewed journal. We excluded all articles that were only available in abstract form.

SYNTHESIS

Data extraction

Two independent reviewers (S.F.L., N.Z.) screened potentially eligible articles, assessed the methodologic quality of each study, and extracted data from included trials. Disagreements were resolved by consensus. For outcomes, pain scores were extracted using the visual analogue scale (VAS) or an alternative numerical pain rating tool. If pain scores were not reported, surrogate measures of effectiveness were included (sleep, function, and quality of life). Frequency of serious and most commonly reported adverse effects was collected. A serious adverse event was based on the definition supplied by Health Canada and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guidance documents.7

Quality assessment

To assess quality, we used the Jadad scale, a 5-item tool scored between 0 and 5.8 We categorized the trials as high or low quality with scores greater than 2 or 2 or lower, respectively.

Literature search results

We found 2269 potentially eligible articles from the search strategy and 10 other potential articles through review of references. Sixteen relevant studies were subjected to full-text review (Figure 1) with one study9 identified later in the references of the College of Family Physicians of Canada guidance document on medical marijuana.10 Altogether, this review identified 6 randomized controlled trials,9,11–15 with 5 of them having crossover designs9,11–14; 1 study was performed primarily for spasticity in multiple sclerosis (MS) with pain evaluated as a secondary outcome.11 We did not identify any historically controlled comparative studies.

Figure 1.
Figure 1.

Articles retrieved through searches

Study characteristics

Five studies were rated as high quality, scoring 3 out of 5.9,12–15 Allocation concealment was reported in 4 studies.9,13–15 Summaries of the final 6 articles in our review are presented in Tables 1 and 2.8,9,11–15

View this table:
Table 1.

Characteristics of the 6 studies in this review that examined the use of medical marijuana for CNCP

View this table:
Table 2.

Summaries of the 6 studies in this review that examined the use of medical marijuana for CNCP

In total, 226 adults (mean age of 45 to 50 years across trials) with chronic neuropathic pain were randomized, with 189 adults specifically identified as having chronic neuropathic pain.9,12–15 Two studies focused on HIV-associated neuropathy,13,15 1 on posttraumatic neuropathy,12 and 2 on mixed neuropathic conditions.9,14 The study involving patients with MS did not discriminate between spasticity pain and neuropathic pain.11 Three studies limited enrolment to patients with previous cannabis exposure,9,14,15 while 2 had no limitations.11,12 All trials excluded individuals with a history of psychotic disorders and previous history of cannabis abuse or dependence. All trials, except 1,15 reported the use of urine toxicology or other screening tools before starting the trial. Pain duration (6 to 9 years) was specifically mentioned in 3 trials,9,14,15 with 4 trials identifying baseline pain in the moderate range.9,12,14,15 Four9,12–14 of the 5 trials9,12–15 that allowed participants to continue to use opioids, anticonvulsants, and antidepressants reported that more than 50% of participants used concomitant opioids. Studies did not report the baseline dose of concurrent analgesics.

Trial duration varied from 17 days11 to 8 weeks,12 with the actual intervention (smoking cannabinoids) varying from a minimum of 3 experimental session days each lasting 6 hours9,14 to a maximum of 5 days.12,13,15 One study had an intervention period of 3 days.11

Only 1 trial administered delta-9-tetrahydrocannabinol (delta-9-THC) through the use of a vaporizer.9 The strength of delta-9-THC employed in the trials for smoked cannabinoids ranged from a low of about 1%9,12 to a high of 9.4%12 as measured by the percentage of dry weight. The total daily delta-9-THC consumption was reported only in 1 trial.14 In 3 studies the total daily delta-9-THC consumption was calculated based on the reported percentage of dry weight delta-9-THC and the cigarette weight.11,12,15 The total daily delta-9-THC exposure could not be determined in 1 study because of missing information13 and in another study owing to flexible dosing.9 The total daily delta-9-THC consumed during the trials ranged between a low of 1.875 mg per day12 and a high of 34 mg per day14 (Table 3).9,11–15

View this table:
Table 3.

Incidence of AEs reported in the 6 studies in this review

The 2 trials open to cannabis-naïve participants reported dropouts or withdrawals owing to potential adverse effects of smoked cannabis11,12 such as psychosis (n= 1), persistent cough (n = 1), feeling “high” (n = 2), dizziness (n = 2), and fatigue (n = 1). Causes for the remaining dropouts in the 5 studies were unrelated to delta-9-THC consumption (eg, personal reasons, withdrawal of consent, medical causes unrelated to cannabis).

Efficacy

A meta-analysis of the efficacy of using delta-9-THC could not be completed owing to the heterogeneity of interventions and outcome variables.

All studies reported a statistically significant benefit in terms of pain relief. Ware et al reported a difference of 0.7 in average daily VAS between the placebo group (score of 6.1) and the 9.4% delta-9-THC intervention group (score of 5.4).12 The cigarettes with the lower delta-9-THC potency (2.5% and 6.0%) were associated with more modest reductions in average daily pain scores of 5.9 and 6.0, respectively.12 Wilsey et al reported statistically significant improvement in the cannabis group for pain reduction over time (0.0035 reduction in VAS per minute),14 noting a ceiling effect with equal antinociception between the high (7%) and low (3.5%) delta-9-THC concentrations. A 2013 study also by Wilsey et al reported similar findings, in which vaporized cannabis provided substantial analgesia compared with placebo, while noting that the 1.29% and 3.53% delta-9-THC doses were equianalgesic to one another.9 While there was a statistically significant mean difference in VAS reduction between the delta-9-THC group and the placebo group in the study involving MS patients, the baseline pain level of participants was low, 14.51 (95% CI 9.16 to 21.75) and 16.61 (95% CI 10.79 to 24.93) in the placebo and intervention groups, respectively.11 Clinically meaningful pain reduction was reported in 3 studies,9,13,15 with 46%, 52%, and 61% of cannabis users reporting benefit versus 18%, 24%, and 26% of the placebo group (Ellis et al,13 Abrams et al,15 and Wilsey et al,9 respectively). The effect of medical marijuana on the dose of other analgesic drugs, including opioids, was reported in 1 study, which noted that opioid doses did not differ statistically significantly from baseline.13 Functional outcomes were absent in all studies; however, 2 studies assessed quality of life and both reported no statistically significant improvement.12,13

Adverse events

While there were no serious adverse events reported in any of the trials, smoking cannabis was associated with a greater incidence of adverse events compared with placebo in each of the studies (Table 3).9,11–15

While all trials captured neurocognitive side effects, only 1 trial reported detailed incidence of adverse effects across multiple organ systems (eg, visual symptoms, gastrointestinal, musculoskeletal).12 Adverse neurologic or psychiatric events (eg, headaches, sedation, dysphoria, and poor concentration) increased with cannabis use versus placebo and with higher delta-9-THC concentrations.12 Another study noted statistically significantly (P < .001) increased incidence of sedation, disorientation, confusion, and dizziness in the cannabis group.15 Wilsey et al reported that feeling “high,” “stoned,” and “impaired” scored statistically greater in the cannabis group compared with the placebo group and appeared to be dose dependent.14 On specific neuropsychological tests, the 7% delta-9-THC concentration was associated with impaired attention, learning, memory, and psychomotor speed, while the 3% delta-9-THC concentration resulted in learning and memory decline.14 For patients using lower doses (1.29% and 3.53%) and a vaporizer, similar effects were noted in a dose-dependent manner for feeling “high,” “stoned,” “drunk,” and “sedated”; however, the effect sizes for all psychoactive outcomes were small.9 In the same study, outcomes of neuropsychological testing noted a general cognitive decline (small effect size) with the greatest effect on learning and memory (small to medium effect size). In the study involving patients with MS, 6% of the delta-9-THC group reported feeling “too high” posttreatment as compared with 0% of the placebo group.11 For noncognitive effects, fatigue, throat irritation, and anxiety were noted in a number of studies.11,13

DISCUSSION

This systematic review found that the use of medical marijuana in the management of CNCP of primarily neuropathic origin was associated with a reduction in pain and a number of short-term neurocognitive adverse effects. While most of the trials were of high quality, the psychoactive effect of delta-9-THC versus inactive placebo resulted in unmasking in many trials. Only 2 studies reported maintaining a positive but smaller effect size when correcting for this factor,9,13 consistent with the finding that inappropriate blinding has been shown to cause larger treatment effects.16

While statistical reduction in pain was reported in all studies, a more fundamental outcome is clinically meaningful pain reduction (a decrease of 2 points on a 0-to-10 numerical pain rating or a 30% improvement in pain intensity), which has been associated with an improvement in a patient’s global impression of change.17,18 Only 3 of the 6 trials evaluated and reported positive findings in this respect. Functional assessment has also been designated as a core outcome domain in CNCP trials,17 but its measurement was absent in all included studies. With quality of life unchanged in 2 trials, the question of whether patients experience functional improvement with medical marijuana remains unanswered. Finally, there was a notable absence of effectiveness trials comparing outcomes with other known treatments in CNCP. Most studies, in fact, employed medical marijuana as an adjunct to participants’ existing opioids and adjuvant medications suggesting it might only have a role in refractory pain in conjunction with other analgesics.

The trials in our review reported short-term psychoactive and neuropsychological effects without evidence of serious adverse effects, measured over hours or days. Of note, one study specifically commented that the small to medium effect sizes of cognitive effects were unlikely to affect daily functioning.9 These cognitive adverse effects in the short term are similar to those experienced with opioids19 and suggest that the same precautions employed with opioids would be in order with the use of medical marijuana. In particular, its use in elderly patients or those with pre-existing cognitive impairments might not be ideal. These short-term findings contrast with a recent review of observational data collected over years reporting several high-confidence-level adverse effects (eg, addiction, diminished life achievement, and motor vehicle accidents).20Analogous to trials of opioids, medical marijuana trials, including those in our review, have been of short duration and not designed to detect longer-term sequelae.21

Finally, the amount of exposure to delta-9-THC in all studies was extremely low in contrast to that available in the marketplace. According to Health Canada’s website, the average amount of dried marijuana dispensed under the old MMAR was 1.0 to 3.0 g per day containing delta-9-THC concentrations of 12.5%.22 With an average dry weight of only 2.0 g per day, the available delta-9-THC exposure under the old MMAR program was 250 mg, or nearly 8-fold the maximum amount used in clinical trials. Now, under the newer regulations (Marihuana for Medical Purposes Regulation), industry producers can provide even higher delta-9-THC concentrations (up to 20% delta-9-THC by dried weight as shown on industry websites), suggesting a potential gap between evidence and product offerings.

Comparison with previous systematic reviews

Previous systematic reviews have assessed the available evidence for the use of cannabinoids in chronic pain23,24; however, none commented systematically on the level of delta-9-THC consumption. The review by Martín-Sánchez and colleagues assessed the use of cannabinoids in chronic pain of any cause, with a third of the trials focused on cancer pain and interventions restricted to synthetic cannabinoids only.23 The authors commented on a positive, moderate, short-term trend toward pain reduction but noted serious adverse effects.

The Lynch and Campbell review on cannabinoids in CNCP included oral or smoked synthetic and natural cannabinoids.24 The authors included 4 trials contained in our review.12–15 While they opined that larger trials were necessary with additional reporting requirements, they concluded that there was support for the use of cannabinoids in CNCP to provide modestly effective and safe treatment.24

Conclusion

The current evidence suggests that very low-dose medical marijuana (< 34 mg/d) is associated with an improvement in refractory neuropathic pain of moderate severity in adults using concurrent analgesics. There were no studies evaluating other CNCP causes including rheumatologic conditions.25 The generalizability of the results in CNCP is limited by factors such as the quality of studies, small sample sizes, very short duration, and dose and scheduling variability. Neurocognitive adverse effects such as learning, memory, and psychomotor deficits are common even with low-dose, short-term use but they appear well tolerated. However, the longer-term consequences of medical marijuana still remain unknown. These findings are consistent with existing guidance documents.10 Future trials should consider incorporation of standard outcome measures beyond pain, such as function and quality of life, similar to other interventions in CNCP.26 It might also be advantageous to enable prospective observational studies through creation of registries, protocols, and mandatory reporting of adverse events. Without additional evidence and a clear understanding as to the indications for and dosing of cannabis, there remains a risk that clinicians might unwittingly propagate similar issues that we now face with opioids in the management of CNCP.

Notes

EDITOR’S KEY POINTS

  • Medical marijuana has been proposed as a potential treatment for use in pain management. However, there is still uncertainty about the specific indications, ideal doses, and adverse effects that are related to this substance when used for medical purposes.

  • While statistical reduction in pain was reported in all studies in this review, a more fundamental outcome is clinically meaningful pain reduction (a decrease of 2 points on a 0-to-10 numerical pain rating or a 30% improvement in pain intensity); only 3 of the 6 studies reported positive findings in this respect. Most of the studies employed medical marijuana as an adjunct to participants’ existing opioids and adjuvant medications, suggesting it might only have a role in refractory pain in conjunction with other analgesics.

  • Neurocognitive adverse effects such as learning, memory, and psychomotor deficits are common even with low-dose, short-term use of medical marijuana but they appear well tolerated. However, the long-term consequences of medical marijuana remain unknown.

POINTS DE REPÈRE DU RÉDACTEUR

  • On a proposé d’utiliser la marijuana médicale comme traitement potentiel de la douleur. Toutefois, on connaît encore mal les indications spécifiques, le dosage idéal et les effets indésirables de cette substance lorsqu’on l’utilise à des fins médicales.

  • Même si toutes les études de cette revue rapportent une réduction significative de la douleur, une réduction cliniquement significative de la douleur (c.-à-d. une diminution de 2 points sur une échelle de la douleur entre 0 et 10 ou une amélioration de 30 % de l’intensité de la douleur) serait une issue plus fondamentale; seulement 3 des 6 études ont rapporté des résultats positifs de cette nature. Dans la plupart des études, on utilisait la marijuana médicale comme complément aux opiacées existants ou à des médications adjuvantes, ce qui suggère qu’elle pourrait n’être utile qu’en association avec d’autres analgésiques.

  • Des effets indésirables d’ordre neurocognitif tels que des troubles d’apprentissage, de mémoire ou de psychomotricité sont fréquents, même avec des doses faibles et pour de courtes périodes, mais ces effets semblent bien tolérés. Toutefois, les conséquences à long terme de la marijuana médicale demeurent inconnues.

Footnotes

  • Cet article a fait l’objet d’une révision par des pairs.

  • This article has been peer reviewed.

  • Contributors

    All authors contributed to the concept and design of the study and data gathering. Ms Lakha, Dr Zoheiry, and Dr Deshpande contributed to the analysis of the study. Dr Deshpande and Dr Mailis-Gagnon contributed to the interpretation of the study and preparing the manuscript for submission.

  • Competing interests

    None declared

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Efficacy and adverse effects of medical marijuana for chronic noncancer pain
Amol Deshpande, Angela Mailis-Gagnon, Nivan Zoheiry, Shehnaz Fatima Lakha
Canadian Family Physician Aug 2015, 61 (8) e372-e381;
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