Guidance for the use of medicinal cannabis in the treatment of chronic non-cancer pain in Australia

Disclaimer: This guidance document was developed in 2017 and reflects the research on medicinal cannabis available up to that time. Clinical guidance is not usually the role of the TGA as a therapeutic goods regulator, however, the information was developed to support medical practitioners at the time. The TGA is discussing potential avenues for updating this research in the future.

Version history

• The clinical guidance documents were developed in 2017 and provide a broad overview of the evidence available at that time to support medicinal cannabis use.
• In February 2020, the National Drug and Alcohol Research Centre reviewed the clinical evidence for the use of medicinal cannabis published in refereed medical journals since the clinical guidance documents were released. Additional relevant studies were included in the bibliographies for epilepsy and pain.
• In November 2024, the clinical guidance documents were updated to reflect current regulatory information.

Important considerations

• Guidance documents are not the same as clinical guidelines. Guidance documents are documents produced to provide advice and further explanations and do not specify requirements that are binding in regulation.
• Healthcare practitioners are encouraged to conduct their own research to ensure their knowledge and prescribing reflects the current state of evidence of medicinal cannabis.

Further information

Visit the TGA’s medicinal cannabis consumer hub for additional information on how the TGA provides legal access to medicinal cannabis products in appropriate circumstances. 

Introduction

In 2017, a set of guidance documents were made available to assist doctors and their patients who choose to prescribe medicinal cannabis in Australia under current access schemes. These were developed based on reviews of available evidence for the use of medicinal cannabis in five different settings. Included is an overview addressing the evidence base for medicinal cannabis therapy generally as well as specific documents relating to medicinal cannabis in the treatment of palliative care, epilepsy, chemotherapy-induced nausea and vomiting (CINV), multiple sclerosis (MS) and chronic pain.

This document reflects the evidence supporting the use of medicinal cannabis in treating chronic pain and the recommendations of the Chronic Pain Working Group.

Note: These guidance documents are based on evidence available at the time of publication and will be updated as new evidence emerges. Each document should be read in conjunction with the 'Guidance to the use of medicinal cannabis in Australia - Overview'.

In September 2017 a workshop was held in Sydney to discuss the review of the available evidence for the use of medicinal cannabis (medicinal cannabis) in patients with chronic non-cancer pain (CNCP). Workshop participants included representatives from consumer groups, medical colleges, special societies and states and territories.

Review method

There has been substantial interest in the potential utility of medicinal cannabis for use in chronic non-cancer pain (CNCP) conditions, which impose considerable burden on patients by adversely affecting multiple facets of their lives. A number of weaknesses of recent systematic reviews of evidence of medicinal cannabis for pain, including those by Whiting and colleagues^[1], and Nugent and colleagues^[2] warranted a new review. These weaknesses varied across studies, but included: a lack of clarity around the pain conditions included; no stratification to consider potential differences in effects of different cannabinoids; no stratification of cannabinoids effects on different CNCP conditions; inclusion of a limited range of cannabinoids; limiting evidence to randomised controlled trials (RCT); a lack of clarity in reporting of pain outcomes; and limited examination of study withdrawals and adverse events. The current review addressed all of these issues.

In 2017, the Australian Government Department of Health commissioned a team from the University of New South Wales, University of Sydney and University of Queensland under the coordination of the National Drug and Alcohol Council (NDARC) to review the available evidence for the use of medicinal cannabis in the above five settings.

The researchers conducted a review of previously published reviews from multiple databases such as Medline, Embase, PsychINFO and EBM Reviews based on PRISMA145. PRISMA is the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, and is an evidence-based minimum set of items for reporting on randomised controlled trials (RCTs). These guidelines have been developed because of concern for low quality trials and aim to improve the quality of medical research, remove bias and improve transparency and accurate reporting of findings. Searches were guided by a specialist Librarian using specific search terms and were limited to studies published between 1980 and early 2017. Two reviewers independently examined titles and abstracts for relevance using Covidence Software and the Cochrane Risk of Bias Tool was used to assess studies, aiming to increase accuracy. The GRADE (grading of recommendations, assessment, development and evaluation) approach, an internationally recognised standard applying to weighting of evidence in scientific and medical literature was used to evaluate the quality of evidence.

In July 2017, the department also convened five separate Working Groups to consider the available evidence for the use of medicinal cannabis in the treatment of each of the settings. The five groups consist of individuals from a wide range of backgrounds and organisations, including senior staff from each state and territory Department of Health, fifteen healthcare professional organisations, clinical staff from twenty-nine hospitals and healthcare systems, fourteen outpatient or Primary Health Networks and eighteen consumer representative groups. The chronic non-cancer pain (CNCP) working group met in Sydney in September 2017.

The working group noted that the available studies were of variable quality, with the design of many at high risk of bias (Appendix 2). The workshop concluded overall that there is evidence of limited efficacy for both plant-based cannabis preparations and for synthetic cannabinoids in some patients with CNCP. However, the workshop noted the generally very modest effect of medicinal cannabis on pain intensity (NDARC analysis of numbers needed to treat (NNT) in one systematic review by Whiting and colleagues^[1], 22 for a 30% reduction and 26 for a 50% reduction in self-reported pain intensity). Put simply, only one person in 22-26 treated with medicinal cannabis would get significant pain relief. The workshop also noted the significant potential for adverse events in patients treated with medicinal cannabis, including reduced physical function, demotivation, tolerance, depression, paranoia, psychosis and loss of intellectual capacity and that available studies were short term, of variable quality and with the design of many at high risk of bias.

The workshop noted that although there was some evidence for improvement in sleep patterns with medicinal cannabis treatment compared with placebo, there was no improvement in overall quality of life with medicinal cannabis. Significantly, there was also no difference in overall physical functioning, a more robust measure of treatment outcome than self-reported visual analogue pain scores.

In the setting of CNCP, potential new pharmacotherapeutic agents such as medicinal cannabis need to be considered alongside established therapeutic approaches. Active self-management strategies, which generally incorporate a reduction in drug utilization (particularly high risk opioids) have a proven place in the treatment of CNCP.

The workshop concluded that although there is evidence of limited efficacy of medicinal cannabis in refractory neuropathic pain when used in conjunction with traditional analgesics, current evidence has not defined a clear place for medicinal cannabis in the treatment of patients with CNCP.

A summary of the cannabanoids used is presented in Table 1.

Conditions characterised by CNCP are varied, and pain is considered by leading researchers to be only one of a range of core outcomes that must be considered in trials of any intervention^[3]. In examining pain, it has been recommended that not only there be a change in pain scores, but also that the reduction is a) meaningful i.e. 30%, or b) substantial, i.e. 50% reduction^[3]. Here, we summarise evidence on the effects of medicinal cannabis on:

1. Pain intensity
   • 30% reduction in pain
   • 50% reduction in pain
   • Changes in continuous pain scores
2. Physical functioning
   • Overall physical functioning
   • Change in sleep problems
   • Change in quality of life
3. Emotional functioning
   • Overall emotional functioning
   • Change in depressive symptoms
   • Change in anxiety symptoms
4. Patient global impression of change
   • Patient global impression of change (PGIC) scale
   • Proportion reporting improvement
5. Withdrawal from the study
   • Including due to adverse events
6. Adverse events
   • Any adverse event
   • Serious adverse events
   • Specific adverse events

A total of 102 studies examined the impact of medicinal cannabis on patients with CNCP. This included 26 parallel RCTs, 23 cross-over RCTS, and 53 observational studies. Some publications included multiple studies, thus the number of references cited herein will not always match the number of studies quoted. The process for selection of studies in the review is displayed in the PRISMA flowchart in Appendix 1.

Table 2 shows the key to grading of quality of evidence for each of the outcomes we have reviewed in this document, based on GRADE4. These grades reflect our confidence in the accuracy of the stated outcomes.

Section 2 summarises findings of studies examining the effects of medicinal cannabis on patients with CNCP. Study withdrawal evidence is summarised in section 6 and adverse events evidence is summarised in section 9.

Note that in this document, the number of included studies is not always the same as the number of publications, as some publications included multiple independent studies.

1. Summary of evidence of effects of MC on patients with CNCP

1.1. Any CNCP condition

A meta-analysis of all randomised studies in CNCP averaging across all medicinal cannabis products indicated that medicinal cannabis was more likely than placebo to produce 30% and 50% reductions in pain scores and more likely than placebo to produce a significantly greater reduction in pain intensity ratings (see Table 3). Nabiximols, nabilone and THC extract, when separately examined, were much less consistently superior to placebo in producing a 30% reduction in pain or reducing average pain intensity. The lack of consistency for some individual cannabinoids probably reflects the small number of trials and their small sample sizes.

Overall, we can be moderately confident that CNCP patients receiving medicinal cannabis are more likely to achieve 30% and 50% reductions in pain and to report a reduction in pain ratings than patients given a placebo. The evidence was strongest for nabiximols, which was the most likely cannabinoid to be associated with reduction in overall pain scores. Single studies of lesser quality suggest that nabilone, cannabis sativa, THC:CBD extracts and ajulemic acid may be more effective than placebo in producing a 30% reduction in pain. However, this evidence is limited by the small number of studies and their small samples which may mean that the therapeutic effect is substantially different from the effects reported to date.

Of the 53 included observational studies of people living with CNCP, seven^[5-10] examined pain outcomes and had a suitable comparison group, and these were entered into a meta-analysis. No observational study with a comparison group examined 30% reduction in pain (Table 4). One study^[7] examined 50% reduction in pain in patients receiving either THC extract, CBD extract or THC:CBD extract compared to placebo, and found no significant evidence of effect. Six studies (three testing nabilone ^[5,8], and three testing cannabis sativa^[6,9,10]) examined change in pain intensity, and found no significant evidence of effect.

We considered all evidence from observational studies as low quality evidence.

1.2. Specific pain conditions

Table 5 summarises the randomised trial evidence for the impact of medicinal cannabis in CNCP upon pain, presented separately for each CNCP condition and each pain outcome. We have highlighted fibromyalgia, neuropathic pain and arthritis as these are commonly discussed CNCP conditions, although it should be noted that the definition of neuropathic pain particularly in these studies was unlikely to have been uniform. We have defined neuropathic pain as pain caused by a lesion or disease of the somatosensory nervous system. This definition was adopted in 2011 and it is therefore possible that studies done before this time included a more heterogenous subject population.

The effects of medicinal cannabis in multiple sclerosis (MS)-related pain has been presented separately, given the number of studies examining pain (neuropathic and non-neuropathic) in MS, so that it is possible to assess the evidence for MS and for non-MS CNCP conditions.

2. Use of THC/CBD combinations or products

One quarter of the studies (N= 26) evaluated the use of THC/CBD combinations in treating CNCP. Nabiximols (2.7mg THC:2.5mg CBD) was tested for the treatment of MS-related neuropathic or other CNCP^{[13,15,21,23,30,66,70,86,88,92,93,98}. It was also trialled for the treatment of ALS-related CNCP31, neuropathic pain of varying aetiology^{[14,20,22,29,32,45,67,77]}, and rheumatoid arthritis^[27]. THC:CBD products were trialled for the treatment of mixed CNCP^[7], Parkinson's Disease-related CNCP^[38], and mixed neuropathic pain^[51].

Standardised dronabinol products were used in 17 studies, primarily for the treatment of mixed CNCP^{[12,18,24,25,28,41,99,100]} or mixed neuropathic pain^{[49,50,61,68,95,96]} and fibromyalgia^{[18, 19]}. Standardised nabilone products were used in 17 studies to treat fibromyalgia^[33,53,101], mixed CNCP^{[8,47,58,65, 82,84]}, and mixed neuropathic pain^{[5,34,35,43,91]}.

3. Dosage and other pharmacological considerations

3.1. Nabiximols

Standardised nabiximols was delivered as an oromucosal spray (Table 1), delivering 2.7mg of THC and 2.5mg of CBD per spray. Nabiximols was most commonly used for the treatment of MS-related pain and spasticity^{[13,15,21,23,30,66,70,86,88,92,93,98,102]}. It was also studied in the treatment of a number of neuropathic pain conditions that included diabetic peripheral neuropathy, chemotherapy-induced neuropathic pain, and peripheral or central neuropathic pain^{[14,20,22,32,67,77,103-105]}. One RCT administered nabiximols as a treatment for pain in rheumatoid arthritis^[27]. Another RCT examined the therapeutic benefit of nabiximols for spasticity and pain in amyotrophic lateral sclerosis (ALS)^[31].

Patients receiving nabiximol for MS-related pain received a total daily dose ranging from 0.81mgTHC / 0.75mg CBD, up to 129.6mg THC /120mg CBD per day (this equates to 0.3 to 48 sprays per day). In randomised trials, total daily doses ranged from 2.7mg THC / 2.5mg CBD, and up to 129.6mg THC /120mg CBD per day (this equates to 1 to 48 sprays per day). Treatment time ranged between 3 and 14 weeks in randomised controlled trials, and 6 to 62 weeks in observational studies.

Patients receiving nabiximols for non-MS related neuropathic pain received a total daily dose ranging from 3.51mg THC / 3.25mg CBD, up to 130mg THC /120mg CBD per day (this equates to 1.3 and 48 sprays per day). Treatment time ranged between 3 and 14 weeks in randomised controlled trials, and 26 to 42 weeks in observational studies.

Patients receiving nabiximols for the treatment of pain from rheumatoid arthritis received a total daily dose ranging from 2.7mg THC /2.5mg CBD to 16.2mg THC /15mg CBD (this equates to between 1 and 6 sprays per day). Treatment duration was 5 weeks. For patients receiving nabiximols for the treatment of pain and spasticity associated with ALS, total daily dose was not reported by study authors. Treatment duration was 6 weeks.

3.2. THC:CBD extracts

THC:CBD extracts were used in four studies of a variety of CNCP conditions that included MS-related pain^[106], pain associated with Parkinson's disease38, mixed neuropathic pain^[51], and mixed CNCP^[7]. The THC:CBD extracts were administered as either standardised capsules or as a sublingual spray (see Table 1). Patients given THC:CBD extracts received a sublingual spray or capsule.

For patients receiving THC:CBD extracts for the treatment of CNCP, total daily dose ranged from 2.5mg THC /2.5mg CBD to 97.5mg THC /97.5mg CBD. Treatment duration ranged between 4 and 12 weeks.

In one study, patients received THC:CBD extracts for the treatment of neuropathic pain, with the total daily dose ranging from 2.5mg THC /2.5mg CBD to 120mg THC /120mg CBD; treatment duration was 2 weeks.

3.3. Dronabinol

Dronabinol was administered as a standardised product in an oral capsule when used to treat mixed CNCP^{[12,24,25,28,41,100,107]}, neuropathic pain^{[50,61,68,95,96]}, spinal cord injury^[49,99,108], and fibromyalgia^{[18, 19]}. For patients receiving dronabinol for the treatment of mixed chronic non-cancer pain, total daily dose ranged from 2.5mg and 60mg. Treatment duration ranged from 1 day, up to 156 weeks in randomised studies, and 4 to 6 weeks in observational studies.

For patients receiving dronabinol for the treatment of neuropathic pain, total daily dose ranged from 2.5mg and 25mg. Treatment duration ranged from 20 days to 8 weeks in randomised studies, and between 8 and 52 weeks for observational studies.

For patients receiving dronabinol for treatment of fibromyalgia, total daily dose ranged from 10mg to 20mg, with a treatment duration of 8 to 12 weeks18,19. These are registered clinical trials without published results; dosage information should be treated with caution.

3.4. THC extract

THC extracts were generally standardised products that were delivered either in an oral capsule, or as an oromucosal spray when used to treat mixed chronic non-cancer pain^{[75,78,83,84]}, fibromyalgia^[89], central neuropathic pain^[37], and multiple sclerosis-related neuropathic or mixed CNCP^{[26,51,109-111]}.

For the treatment of MS-related neuropathic or other pain, patients received a total daily dose of THC extract ranging between 2.5mg and 120mg. Treatment duration ranged between 2 days and 12 weeks in randomised studies, and 108 weeks in observational studies.

For the treatment of non-MS related CNCP, THC extract total daily dose in observational studies ranged between 2.5mg and 50mg, and treatment duration ranged between 2 and 20 weeks.

In one study for the treatment of central neuropathic pain, total daily dose of THC extract was a maximum of 129.6mg; treatment duration was 2 weeks.

One study used THC extract for the treatment of pain associated fibromyalgia. Total daily dose ranged between 2.5mg and 15mg, and treatment duration was 12 weeks.

3.5. Nabilone

Nabilone was delivered as a standardised oral capsule when used to treat pain due to fibromyalgia^{[33,101,112,113]}, chronic non-cancer pain^{[8,47,58,65,82,84,114]}, and peripheral, diabetes-related and multiple-sclerosis-related neuropathic pain^{[5,35,43,91,115]}. Nabilone total daily dose ranged between 0.25mg and 8mg. In randomised studies, total daily dose ranged between 0.25mg and 1mg, and treatment duration was between 4 and 8 weeks. In observational studies, treatment duration ranged between 4 and 16 weeks.

For the treatment of mixed neuropathic pain, nabilone total daily dose ranged between 0.25mg and 4mg. Treatment duration ranged between 4 and 9 weeks in randomised studies, and went for 26 weeks in observational studies.

For the treatment of pain due to fibromyalgia, nabilone total daily dose ranged between 0.5mg and 2mg. In randomised studies, treatment duration ranged between 2 and 4 weeks. One observational study followed patients for 52 weeks.

3.6. CBD extract

The two observational studies^[7,116] that used CBD extracts to treat generalised chronic non-cancer pain delivered the CBD extract either as a standardised sublingual spray or as an oral capsule. Total daily dose of CBD extract ranged between 25mg and 150mg, and treatment duration lasted 12 weeks.

3.7. Cannabis sativa

Cannabis sativa was used in 26 studies to treat a number of pain conditions that included central or peripheral and HIV-related neuropathic pain^{[11,42,52,55,56,87,117]}, fibromyalgia^[71,72], Multiple sclerosis-related chronic non-cancer pain^[40,118], Parkinson's disease related chronic non-cancer pain^[73,80], and generalised chronic non-cancer pain and neuropathic pain conditions^{[6,10,54,59,62,63,69,74,76,79,94]}. Cannabis sativa was less often used as a standardised product but some studies reported using standardised medicinal cannabis products. Some cannabis sativa was grown and harvested under the supervision of the US National Institute on Drug Abuse.

Cannabis sativa was administered primarily as a herbal cigarette. In some cases, the cannabis was vapourised or administered through buccal absorption or oral ingestion. Dose ranges were less precise when herbal cannabis sativa was used. Dose was sometimes reported as the weight of cannabis cigarette, or by the THC-content of the cigarette.

For the treatment of chronic non-cancer pain, total daily dose of cannabis sativa (when reported) ranged between 0.9g and 13.4g of plant material. In one crossover trial, patients were administered 800mg of plant material that contained 4% THC. Treatment duration for this trial was 3 days. In observational studies, treatment duration ranged between 1 day and 4 years.

For the treatment of neuropathic pain, total daily dose of cannabis sativa (when reported) ranged between 3 and 4mg of plant material containing between 1% and 12.5% THC. In randomised studies, treatment duration ranged between 1 and 5 days. In non-randomised studies, treatment duration ranged between 1 day and 6 months.

Two observational studies reported total daily dose of cannabis sativa (when reported) ranged between 60mg and 120mg for the treatment of pain associated with fibromyalgia. Treatment duration ranged from 2 months to multiple years.

3.8. Ajulemic Acid

Ajulemic acid (CT-3) was administered as a standardised oral capsule in one study^[44] of mixed neuropathic pain. The dosage range was 20mg to 40mg administered twice per day. Treatment duration was one week.

4. Place in the therapeutic hierarchy

To determine the role of medicinal cannabis in treating CNCP, trials would need to compare cannabinoids to first and second-line treatment and no therapy. Trials would also be required to assess the role of medicinal cannabis as adjunctive treatment e.g. use in addition to other analgesics.

Data on other whether medicinal cannabis was examined alone or alongside other drugs, allowing some ascertainment of the place in the therapeutic hierarchy. Of the 102 included studies, four examined medicinal cannabis as a first-line therapy, and 81 examined medicinal cannabis as a second-line therapy in addition to existing medication regimens. In 17 studies, the place of medicinal cannabis in the therapeutic hierarchy was not reported or could not be determined.

4.1. Evidence for cannabinoids as first-line therapy in CNCP

In the four studies (n = 48 participants) where the cannabinoid was used as first-line therapy^{[49,50,89,101]}, two examined patients with fibromyalgia^[89,101] and two examined patients with neuropathic pain (one of which was MS-related neuropathic pain^[50], and one neuropathic pain related to spinal cord injury^[49]). In these four studies, patients were required to titrate off regular pain medication between one to three weeks before the baseline period and cannabinoid therapy commenced. Average treatment length was 10 weeks. In one of these trials, pain medication (a combination of 5mg oxycodone and 325mg acetaminophen) was provided to manage breakthrough pain throughout the trial^[49].

None of the four studies in which medicinal cannabis was used as first line treatment examined 30% reduction in pain as an outcome. Two studies examined 50% reduction in pain. The cross-over RCT by Svendsen and colleagues^[50] found that the odds of achieving 50% reduction in pain with medicinal cannabis was times greater than with placebo, however this was not significant (95% confidence interval 0.75 to 82.13), and when examined in a sensitivity test, this outcome did not differ from studies where the cannabinoid was used as second line therapy. In the non-randomised pilot study by Schley and colleagues^[89] all four participants who completed cannabinoid therapy over three months reported pain relief of more than 50%. In the retrospective chart review by Chung and colleagues^[101], authors simply stated that five out of six fibromyalgia patients reported continued pain relief.

Only one study where the cannabinoid was administered as first line therapy examined changed in analgesic or opioid use. Rintala and colleagues^[49] reported that 3 out of 7 (43%) participants with neuropathic pain following spinal cord injury used the rescue medication (a combination of 5 mg oxycodone and 325 mg acetaminophen) to manage breakthrough pain throughout the trial.

4.2. Evidence for cannabinoids as second-line therapy in CNCP

Of the 81 studies that evaluated cannabinoids as second line therapy in addition to existing medication, there was often little discussion of the role of other drugs and their potential role in the reported therapeutic outcomes and adverse events. This is important given that many of the drugs have their own benefit and side effect profile that may overlap with those for medicinal cannabis, making interpretation of the study data difficult.

Of the studies that did describe other drug use, there was a varied picture depending on the primary pain condition. In studies examining medicinal cannabis in people with neuropathic pain, concomitant use of analgesics including paracetamol, carbamazepine, gabapentin, metamizole, pregabalin and opioids (e.g. hydromorphone, tramadol, morphine and codeine) was reported. Some studies also reported use of muscle relaxants (e.g. baclofen and clonazepam); non-steroidal anti-inflammatory drugs (NSAIDs; e.g. ibuprofen); and antidepressants (duloxetine, nortriptyline and clomipramine).

For studies examining people with fibromyalgia, common concomitant medications included opioids (e.g. tramadol and tapentadol), antidepressants (e.g. serotonin–norepinephrine reuptake inhibitors (SNRIs; e.g. duloxetine and amitriptyline) and a wide range of other medications such as NSAIDs, anxiolytics, and myorelaxants.

For the single study examining persons with arthritis, concomitant medications included NSAIDs, prednisone and disease-modifying antirheumatic drugs (DMARDs).

For studies of people with mixed CNCP conditions, commonly used concomitant analgesics included opioids (e.g. methadone, morphine, oxycodone, hydrocodone, and hydromorphone); NSAIDs; paracetamol, and antidepressants.

In studies of people with MS-related pain, concomitant medications also included anti-spasticity agents (e.g. baclofen, gabapentin and tizanidine); physiotherapy was also a cooccurring intervention in some studies.

Several studies of people with Parkinson's disease also reported patient use of anti-Parkinsonian medication such as co-careldopa, co-bendeldopa, ropinirole, pramipexole, pergolide and cabergoline.

Changes in analgesic or opioid use were rarely measured in the studies where the cannabinoid was administered as a second line treatment. We have summarised the limited evidence in these studies in the following sections.

4.3. Potential opioid-sparing effects of medicinal cannabis use in CNCP

Two observational studies where cannabis sativa was administered as second line therapy in CNCP examined change in use of regular opioid medication^[62,87]. Both studies examined cannabis sativa and were observational with no comparison group (one study was a crosssectional survey^[62], the other was a prospective survey^[87]); neither had a comparison group.

The cross-sectional survey by Boehnke and colleagues^[62] that examined cannabis sativa for CNCP reported that of the 185 people who completed the survey, the mean (SD) decrease in regular opioid medication use was 64% (45%) after using cannabis sativa.

The prospective survey by Robinson and colleagues^[87] that examined cannabis sativa for diabetes-related neuropathic pain reported that 8 out of 18 patients (44%) stopped using their opioid medication, and the mean (SD) reduction of opioids, expressed in standard units was 4 (0.8).

4.4. Potential other analgesic-sparing effects of medicinal cannabis use in CNCP

Six studies^{[14,15,22,75,98,103]} where medicinal cannabis was administered as second line therapy for CNCP examined change in the use of other analgesic medication. Five studies^{[14,15,22,98,103]} were parallel randomised controlled trials, all of which examined change in use of analgesic medication for breakthrough pain when using nabiximols. These data were amenable to metaanalysis, and there was a significant reduction in the frequency of use of rescue analgesics (SMD -0.13, 95% CI -0.26 to -0.01, I2 =48%) when using nabiximols. Our confidence in this outcome was moderate.

The observational study^[75] examined decrease in concomitant analgesic requirements using the Treatment Outcomes of Pain Survey (TOPS) among persons using THC extract for CNCP. Following treatment, the mean score (on a scale of 0-10, with lower scores indicating less reduction in analgesic requirements, and 10 indicating maximum reduction) was 3 (SD=3.6), indicating a marginal effect.

5. Summary of evidence of effects of medicinal cannabis use on physical functioning, emotional functioning and patients' global impression of change in CNCP patients

Some of the included studies also presented data on outcomes for physical functioning (n=49 studies), emotional functioning (n=39 studies) and participant ratings of global improvement and satisfaction with treatment (n=24 studies). Summaries of these outcomes are provided in Tables 6-8.

Patients receiving any cannabinoid reported no change in overall physical functioning compared with placebo on measures such as the General Health Questionnaire [GHQ], the SF-36 and EQ-5D, see Table 6. There was some evidence that patients receiving nabilone had significantly improved physical functioning but confidence in this outcome was very low. The lack of consistency for some individual cannabinoids probably reflects the small number of trials and their small sample sizes.

Patients receiving any medicinal cannabis product reported a significant reduction in sleep problems compared with placebo (including sleep disturbance and poor sleep quality) but confidence in this estimate was low (Table 6). Reductions in sleep problems were identified for nabiximols and nabilone but confidence in these effects varied and data were not reported for many specific cannabinoids.

Patients receiving any cannabinoid reported no more change in quality of life than with placebo.

Patients receiving any cannabinoid did not report any change in overall emotional functioning or improvement in depressive or anxiety symptoms specifically (see Table 7). A significant improvement in emotional functioning was identified for dronabinol but this was based on a single study and so confidence in this effect is low.

Patients receiving any medicinal cannabis product reported increases on the 7-item patient global impression of change scale (PGIC), and had slightly increased odds of reporting improvement than patients who received placebo (see Table 8). Confidence in these outcomes was low to very low. Most of the evidence was for nabiximols, with some evidence for nabilone, cannabis sativa and THC extract but no other cannabinoids.

6. Tolerability of and withdrawal from treatment

In the studies reviewed medicinal cannabis appeared to be well tolerated by CNCP patients for a limited time period, however patients who received medicinal cannabis were more likely to withdraw from the trials for any reason, includingbecause of adverse events.

Averaged across trials, CNCP patients who received a cannabinoid had two times the odds of withdrawing for any reason from a trial than patients who received placebo and they had 3.34 times the odds of withdrawing because of adverse events. CNCP patients receiving placebo were slightly more likely to withdraw from trials because of a lack of efficacy than those receiving medicinal cannabis. There was some variation between medicinal cannabis products in reasons for withdrawal.

7. Reviewing a patient's response to medicinal cannabis

Given the short duration of most clinical trials, there is little evidence to guide decisions about when to review treatment. Most randomised and clinical observational studies ran for less than 12 weeks, but a small number of observational studies evaluated safety and efficacy for twelve months or longer^[10,12,101]. These studies evaluated whether patients were still receiving therapeutic benefit from cannabinoids but they did not provide guidance on the circumstances in which patients should stop using the product.

8. Recommended process for auditing patient outcomes

In the published evidence, the treatment outcomes that have been assessed in the effectiveness of medicinal cannabis in the treatment of CNCP include:

1. Change in pain intensity
2. Change in physical functioning
3. Change in emotional functioning
4. Participant ratings of global improvement and satisfaction with treatment.

These outcomes are based on recommendations by the IMMPACT group^[3] for more complete reporting of patient experience across a range of outcomes. They include the impact of pain and pain management on patient functioning and quality of life.

9. Adverse events, drug-drug interactions, or patient groups for whom the product may pose particular risks

Studies of adverse effects found that CNCP patients taking medicinal cannabis had 2.3 times the odds of experiencing an adverse event and 2.5 times the odds of a serious adverse event compared with taking placebo. These odds were significantly influenced by single studies of dronabinol and THC:CBD extracts. Serious adverse events were reported in a smaller number of studies.

*An odds ratio is not estimable if there are no events in either the intervention or comparison group.

There is little evidence to provide clinical guidance on drug-drug interactions. If cannabinoids are to be used in conjunction with other adjunctive therapies, clinicians and patients should be aware of common adverse events associated with cannabinoid use and consider whether these events are likely to interfere with quality of life beyond any reduction in pain produced by the cannabinoid.

Appendix 1. Study flowcharts

Figure A1.1: Overall study PRISMA flowchart

Figure A1.2: PRISMA flowchart for pain review of reviews

Text version of Figure A1.2

Appendix 2. Quality of current evidence

GRADE ratings of study methodology

For all included studies, we assessed the underlying study methodology using GRADE ratings^[4] whereby randomised controlled trials started with a high rating and were downgraded if important limitations were identified in the study methodology, and observational studies started with a low rating and were upgraded if important strengths were identified.

Of the 26 included parallel randomised controlled trials, 16^[11-26] retained the high study methodology rating, and 10^[27-36] were downgraded to a moderate rating for several reasons. This included small sample sizes, and potential selection bias due to inclusion criteria requiring participants to achieve at least a 20% reduction in pain outcomes after single blind treatment of the cannabinoid being tested^[30,34].

Of the 23 included randomised cross-over trials^[37-58], 22 were downgraded to a moderate rating due to small sample sizes, and one was double downgraded to a low rating due to both a small sample size and a potential conflict of interest as the trial was funded by a pharmaceutical company^[39].

Of the 53 included observational studies^{[5-7, 9,10,16,17,39,45,46,48,51,59-95]}, none were upgraded and so retained the rating of low, and 22 were downgraded to very low^{[6,9,34,45,60,62-65,67,69,71-74,79,81,84,94,96]} for reasons including having a rating of 'serious' or 'critical' in at least one of the risk of bias domains (described below) and having very small sample sizes (such as case series and N-of-1 studies).

Risk of bias in included studies

We additionally assessed the risk of bias in included studies, using the Cochrane Collaboration risk of bias tools for randomised trials and observational studies^[97]. Randomised controlled trials were assessed for risk of bias across six domains: random sequence generation, allocation concealment, blinding of participants and providers (separately for objective and subjective outcomes), blinding of outcome assessors (separately for objective and subjective outcomes), incomplete outcome data and selective reporting.

Observational studies were assessed as having either no risk, moderate risk, serious risk or critical risk across seven domains: bias due to confounding, bias in selection of participants into the study, bias in measurement of interventions, bias due to departure from intended interventions, bias due to missing data, bias in measurement of outcomes, and bias in the selection of the reported result. 'No information' was used when risk could not be determined. Based on these domains, an overall risk of bias judgement was made for each study.

Risk of bias in randomised controlled trials

Of the 49 studies that used a randomised controlled design (including 26 parallel and 23 cross-over randomised controlled trials), most studies were at low risk of bias for random sequence generation (n = 32 studies) and allocation concealment (n = 27 studies), with the remainder judged as unclear due to lack of information. Most studies had either low (n = 21) or unclear (n =25) risk of bias for participant blinding, with only 3 judged as high risk (as participants correctly guessed their treatment). For blinding of outcome assessors, most studies had either low (n = 17) or unclear (n = 29) risk of bias, and 3 were judged as high risk as the outcome assessors were not blinded and were aware to the treatment participants were receiving. Outcome data were mostly complete in the included trials, with 30 studies judged as low risk and 16 as unclear risk for this domain. Three studies were judged to be of high risk for incomplete outcome data, due to substantial and differential dropout between the treatment and comparison groups. Most studies were of either low (n = 23) or unclear (n = 15) risk of bias due to selective reporting, however 11 studies were judged to be of high risk for this domain. Reasons for this high risk rating included omission of reporting of data on outcomes listed as being measured; omission of measures of statistical uncertainty (such as confidence intervals) or effect estimates from statistical tests; changes in selection of the primary endpoint after commencement of the study; or a lack of accounting for within-subjects effects in crossover studies.

Risk of bias in observational studies

Of the 53 included observational studies, 28 were at serious or critical risk of bias due to confounding, primarily due to a lack of adjustment for important domains such as selfselection, high dropout and other drug use. A similar number (n = 29) were at serious or critical risk of bias due to selection of participants into the study, most of whom were selected based on their existing use of cannabinoids. Almost half the studies (n = 25) were at low risk of bias for measurement of the intervention, however 13 were judged to be of serious risk of bias mostly due to poor definition of the cannabinoids studied and the doses used (particularly for studies where patients retrospectively self-reported their use of cannabinoids). Bias due to departure from the intended intervention was mostly not reported, and accordingly 32 studies were judged as having no information for this domain. Of studies where information was available, 15 were judged as having serious or critical risk due to substantial variations in participants' use of the cannabinoids over time (such as intermittent use), and lack of control for use of other substances. In 20 studies, there was insufficient information to determine risk of bias due to missing data, however where information was available, 23 were judged as being at serious or critical risk of bias due to very high dropout, lack of accounting for missing data in analyses, or analyses only being conducted on the small proportion of people who continued therapy. Bias in the measurement of interventions was serious or critical in 23 studies, mostly due to use of subjective measures when participants were unblinded to the treatments they were receiving. Bias due to selection of the reported result was serious or critical in 22 studies where authors only presented selective outcomes, or outcomes for select groups of participants. Overall, of the 53 observational studies, no studies were judged to be of low risk of bias, 6 were judged to be at a moderate risk of bias, 16 were serious, 21 were critical and for 10 there was insufficient information available to make a judgement.

Footnotes

1. Whiting, P.F., et al., Cannabinoids for medical use: A systematic review and meta-analysis. JAMA, 2015. 313: 2456-2473.
2. Nugent, S.M., et al., The effects of cannabis among adults with chronic pain and an overview of general harms: A systematic review. Annals of Internal Medicine, 2017. 167: 319-331.
3. Turk, D.C., et al., Core outcome domains for chronic pain clinical trials: IMMPACT recommendations. Pain, 2003. 106: 337-345.
4. Schünemann, H., et al., GRADE handbook. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach: The GRADE Working Group, 2013.
5. Bestard, J.A. and C.C. Toth, An open-label comparison of nabilone and gabapentin as adjuvant therapy or monotherapy in the management of neuropathic pain in patients with peripheral neuropathy. Pain Pract, 2011. 11: 353-68.
6. Degenhardt, L., et al., Experience of adjunctive cannabis use for chronic non-cancer pain: findings from the Pain and Opioids IN Treatment (POINT) study. Drug Alcohol Depend, 2015. 147: 144-50.
7. Notcutt, W., et al., Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 'N of 1' studies. Anaesthesia, 2004. 59: 440-452.
8. Pinsger, M., et al., Benefits of an add-on treatment with the synthetic cannabinomimetic nabilone on patients with chronic pain--a randomized controlled trial. Wiener Klinische Wochenschrift, 2006b. 118: 327-335.
9. Shah, A., J. Craner, and J.L. Cunningham, Medical cannabis use among patients with chronic pain in an interdisciplinary pain rehabilitation program: Characterization and treatment outcomes. J Subst Abuse Treat, 2017. 77: 95-100.
10. Ware, M.A., et al., Cannabis for the Management of Pain: Assessment of Safety Study (COMPASS). The journal of pain : official journal of the American Pain Society, 2015. 16: 1233-42.
11. Abrams, D.I., et al., Cannabis in painful HIV-associated sensory neuropathy A randomized placebo-controlled trial. Neurology, 2007. 68: 515-521.
12. Ball, S., et al., The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial: a randomised double-blind placebo-controlled parallel-group multicentre trial and economic evaluation of cannabinoids to slow progression in multiple sclerosis. Health Technol Assess, 2015. 19: vii-viii, xxv-xxxi, 1-187.
13. Collin, C., et al., A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurological research, 2010. 32: 451‑459.
14. GW Pharmaceuticals Ltd. A Study of Sativex® for Pain Relief Due to Diabetic Neuropathy. NCT00710424 2008 [cited 2017 July 20]; Available from: https://ClinicalTrials.gov/show/NCT00710424.
15. GW Pharmaceuticals Ltd. A Study to Evaluate the Effects of Cannabis Based Medicine in Patients With Pain of Neurological Origin. NCT01606176 2012 [cited 2017 July 20]; Available from: https://ClinicalTrials.gov/show/NCT01606176.
16. Hagenbach, U., et al., The treatment of spasticity with [Delta] 9-tetrahydrocannabinol in persons with spinal cord injury. Spinal cord, 2007. 45: 551.
17. Langford, R., et al., A double-blind, randomized, placebo-controlled, parallel-group study of THC/ CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis. Journal of neurology, 2013. 260: 984-997.
18. NCT00176163, Supporting effect of dronabinol on behavioral therapy in fibromyalgia and chronic back pain. 2005.
19. NCT01149018, Efficacy Trial of Oral Tetrahydrocannabinol in Patients With Fibromyalgia. 2010.
20. Nurmikko, T.J., et al., Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain®, 2007. 133: 210-220.
21. Rog, D.J., et al., Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology, 2005. 65: 812-9.
22. Serpell, M., et al., A double-blind, randomized, placebo-controlled, parallel group study of THC/ CBD spray in peripheral neuropathic pain treatment. Eur J Pain, 2014. 18: 999-1012.
23. Wade, D.T., et al., Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Multiple Sclerosis Journal, 2004. 10: 434-441.
24. Wong, B.S., et al., Pharmacogenetic trial of a cannabinoid agonist shows reduced fasting colonic motility in patients with nonconstipated irritable bowel syndrome. Gastroenterology, 2011. 141: 1638-1647. e7.
25. Zajicek, J., et al., Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. The lancet, 2003. 362: 1517-1526.
26. Zajicek, J.P., et al., Multiple sclerosis and extract of cannabis: results of the MUSEC trial. Journal of Neurology, Neurosurgery & Psychiatry, 2012. 83: 1125-1132.
27. Blake, D.R., et al., Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford), 2006. 45: 50-2.
28. de Vries, M., et al., Tetrahydrocannabinol Does Not Reduce Pain in Patients With Chronic Abdominal Pain in a Phase 2 Placebo-controlled Study. Clin Gastroenterol Hepatol, 2017. 15: 1079-1086.e4.
29. GW Pharmaceuticals Ltd. A Study of Cannabis Based Medicine Extracts and Placebo in Patients With Pain Due to Spinal Cord Injury. NCT01606202 2012 [cited 2017 July 20]; Available from: https://ClinicalTrials.gov/show/NCT01606202.
30. Novotna, A., et al., A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex((R)) ), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur J Neurol, 2011. 18: 1122-31.
31. Riva, N., et al., The canals study: A randomized, double-blind, placebo-controlled, multicentre study to assess the safety and efficacyon spasticity symptoms of a cannabis sativa extract in motor neuron disease patients. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2016. 17: 44.
32. Selvarajah, D., et al., Randomized placebo-controlled double-blind clinical trial of cannabis-based medicinal product (Sativex) in painful diabetic neuropathy: depression is a major confounding factor. Diabetes Care, 2010. 33: 128-30.
33. Skrabek, R.Q., et al., Nabilone for the treatment of pain in fibromyalgia. J Pain, 2008. 9: 164-73.
34. Toth, C., et al., An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain. Pain, 2012. 153: 2073-82.
35. Turcotte, D., et al., Nabilone as an adjunctive to gabapentin for multiple sclerosis-induced neuropathic pain: a randomized controlled trial. Pain Medicine, 2015. 16: 149-159.
36. van Amerongen, G., et al., Effects on Spasticity and Neuropathic Pain of an Oral Formulation of delta9-Tetrahydrocannabinol in Patients With Progressive Multiple Sclerosis. Clinical Therapeutics, 2017. [Early view].
37. Berman, J.S., C. Symonds, and R. Birch, Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. Pain, 2004. 112: 299-306.
38. Carroll, C.B., et al., Cannabis for dyskinesia in Parkinson disease: a randomized double-blind crossover study. Neurology, 2004. 63: 1245-50.
39. Chung, S.A., et al., Can the cannabinoid nabilone help with pain and sleep in fibromyalgia patients?. Sleep, 2009. 32: A325-A326.
40. Corey-Bloom, J., et al., Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. Canadian Medical Association Journal, 2012. 184: 1143-1150.
41. de Vries, M., et al., Single dose delta-9-tetrahydrocannabinol in chronic pancreatitis patients: analgesic efficacy, pharmacokinetics and tolerability. Br J Clin Pharmacol, 2016. 81: 525-37.
42. Ellis, R.J., et al., Smoked medicinal cannabis for neuropathic pain in HIV: A randomized, crossover clinical trial. Neuropsychopharmacology, 2009. 34: 672-680.
43. Frank, B., et al., Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: Randomised, crossover, double blind study. BMJ, 2008. 336: 199-201.
44. Karst, M., et al., Analgesic Effect of the Synthetic Cannabinoid CT-3 on Chronic Neuropathic Pain: A Randomized Controlled Trial. Journal of the American Medical Association, 2003. 290: 1757-1762.
45. Lynch, M.E., P. Cesar-Rittenberg, and A.G. Hohmann, A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. Journal of Pain and Symptom Management, 2014. 47: 166-173.
46. Narang, S., et al., Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. The Journal of Pain, 2008. 9: 254-264.
47. Pini, L.A., et al., Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active-controlled, randomized trial. The journal of headache and pain, 2012. 13: 677-684.
48. Pinsger, M., et al., Benefits of an add-on treatment with the synthetic cannabinomimetic nabilone on patients with chronic pain--a randomized controlled trial. Wiener Klinische Wochenschrift, 2006. 118: 327-335.
49. Rintala, D.H., et al., Effect of dronabinol on central neuropathic pain after spinal cord injury: a pilot study. American journal of physical medicine & rehabilitation, 2010. 89: 840-848.
50. Svendsen, K.B., T.S. Jensen, and F.W. Bach, Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ, 2004. 329: 253.
51. Wade, D.T., et al., A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms - cross over study. Clinical rehabilitation, 2003. 17: 21-29.
52. Wallace, M.S., et al., Efficacy of inhaled cannabis on painful diabetic neuropathy. The Journal of Pain, 2015. 16: 616-627
53. Ware, M.A., et al., The effects of nabilone on sleep in fibromyalgia: results of a randomized controlled trial. Anesthesia & Analgesia, 2010. 110: 604-610.
54. Ware, M.A., et al., Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. Canadian Medical Association Journal, 2010. 182: E694-E701.
55. Wilsey, B., et al., Low-dose vaporized cannabis significantly improves neuropathic pain. The Journal of Pain, 2013. 14: 136-148.
56. Wilsey, B., et al., A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. The Journal of Pain, 2008. 9: 506-521.
57. Wilsey, B., et al., An Exploratory Human Laboratory Experiment Evaluating Vaporized Cannabis in the Treatment of Neuropathic Pain From Spinal Cord Injury and Disease. Journal of Pain, 2016. 17: 982-1000.
58. Wissel, J., et al., Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain. Journal of neurology, 2006. 253: 1337-1341.
59. Aggarwal, S.K., et al., Characteristics of patients with chronic pain accessing treatment with medical cannabis in Washington State. J Opioid Manag, 2009. 5: 257-86.
60. Allegretti, J.R., et al., Marijuana use patterns among patients with inflammatory bowel disease. Inflamm Bowel Dis, 2013. 19: 2809-14.
61. Attal, N., et al., Are oral cannabinoids safe and effective in refractory neuropathic pain? Eur J Pain, 2004. 8: 173-7.
62. Boehnke, K.F., E. Litinas, and D.J. Clauw, Medical Cannabis Use Is Associated With Decreased Opiate Medication Use in a Retrospective Cross-Sectional Survey of Patients With Chronic Pain. J Pain, 2016. 17: 739-44.
63. Bonn-Miller, M.O., et al., Self-reported cannabis use characteristics, patterns and helpfulness among medical cannabis users. Am J Drug Alcohol Abuse, 2014. 40: 23-30.
64. Brady, C.M., et al., An open-label pilot study of cannabis-based extracts for bladder dysfunction in advanced multiple sclerosis. Mult Scler, 2004. 10: 425-33.
65. Cameron, C., D. Watson, and J. Robinson, Use of a synthetic cannabinoid in a correctional population for posttraumatic stress disorder-related insomnia and nightmares, chronic pain, harm reduction, and other indications: a retrospective evaluation. J Clin Psychopharmacol, 2014. 34: 559-64.
66. Centonze, D., et al., Lack of effect of cannabis-based treatment on clinical and laboratory measures in multiple sclerosis. Neurol Sci, 2009. 30: 531-4.
67. Cimas-Hernando, I., et al., [Assessment of the effectiveness and safety of Sativex(R) in compassionate use]. Rev Neurol, 2015. 60: 202-6.
68. Clermont-Gnamien, S., et al., [The therapeutic use of D9-tetrahydrocannabinol (dronabinol) in refractory neuropathic pain]. Utilisation therapeutique du D9-tetrahydrocannabinol (dronabinol) dans les douleurs neuropathiques refractaires., 2002. 31: 1840-5.
69. Eisenberg, E., M. Ogintz, and S. Almog, The pharmacokinetics, efficacy, safety, and ease of use of a novel portable metered-dose cannabis inhaler in patients with chronic neuropathic pain: A phase 1a study. Journal of Pain and Palliative Care Pharmacotherapy of Pain and Palliative Care Pharmacotherapy
70. Ferre, L., et al., Efficacy and safety of nabiximols (Sativex((R))) on multiple sclerosis spasticity in a real-life Italian monocentric study. Neurol Sci, 2016. 37: 235-42.
71. Fiz, J., et al., Cannabis use in patients with fibromyalgia: effect on symptoms relief and health-related quality of life. PLoS One, 2011. 6: e18440.
72. Gerardi, M.C., et al., Efficacy of cannabis flos in patients with fibromyalgia: A monocentric observational study. Arthritis and Rheumatology,, 2016. 68: 72-74.
73. Gurevich, T., et al., Effect of medical cannabis in Parkinson's disease: Survey of patient experiences. Movement Disorders, 2015. 30: S88-S89.
74. Haroutiunian, S., et al., Evaluation of pain and health-related quality of life (HRQOL) outcomes in chronic pain patients treated with cannabis. European Journal of Pain Supplements, 2011. 5: 277.
75. Haroutiunian, S., et al., Open-label, add-on study of tetrahydrocannabinol for chronic nonmalignant pain. Journal of pain & palliative care pharmacotherapy, 2008. 22: 213-217.
76. Haroutounian, S., et al., The Effect of Medicinal Cannabis on Pain and Quality-of-Life Outcomes in Chronic Pain: A Prospective Open-label Study. Clin J Pain, 2016. 32: 1036-1043.
77. Hoggart, B., et al., A multicentre, open-label, follow-on study to assess the long-term maintenance of effect, tolerance and safety of THC/CBD oromucosal spray in the management of neuropathic pain. Journal of Neurology, 2015. 262: 27-40.
78. Holdcroft, A., et al., Pain relief with oral cannabinoids in familial Mediterranean fever. Anaesthesia, 1997. 52: 483-486.
79. Ko, G.D., et al., Medical cannabis - the Canadian perspective. Journal of pain research, 2016. 9: 735.
80. Lotan, I., et al., Cannabis (medical marijuana) treatment for motor and non-motor symptoms of Parkinson disease: An open-label observational study. Clinical neuropharmacology, 2014. 37: 41-44.
81. Martínez-Rodríguez, J.E., et al., Cannabis use in Spanish patients with multiple sclerosis: Fulfilment of patients' expectations? Journal of the neurological sciences, 2008. 273: 103-107.
82. Martyn, C., L. Illis, and J. Thom, Nabilone in the treatment of multiple sclerosis. The Lancet, 1995. 345: 579.
83. Maurer, M., et al., Delta-9-tetrahydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial. European archives of psychiatry and clinical neuroscience, 1990. 240: 1-4.
84. Notcutt, W., et al., A retrospective description of the use of nabilone in uk clinical practice - extension study (conference poster). Multiple Sclerosis, 2014. September: 468.
85. Palmieri, B., C. Laurino, and M. Vadala, Short-term efficacy of CBD-enriched hemp oil in girls with dysautonomic syndrome after human papillomavirus vaccination. Israel Medical Association Journal, 2017. 19: 79-84.
86. Paolicelli, D., et al., Long-Term Data of Efficacy, Safety, and Tolerability in a Real-Life Setting of THC/CBD Oromucosal Spray-Treated Multiple Sclerosis Patients. J Clin Pharmacol, 2016. 56: 845-51.
87. Robinson, D., A. Garti, and M. Yassin, Cannabis treatment of diabetic neuropathy: Treatment effect and change in health over a 6 month period. Foot and Ankle Surgery, 2016. 22: 58.
88. Rog, D.J., T.J. Nurmikko, and C.A. Young, Oromucosal delta9-tetrahydrocannabinol/ cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial. Clin Ther, 2007. 29: 2068-79.
89. Schley, M., et al., Delta-9-THC based monotherapy in fibromyalgia patients on experimentally induced pain, axon reflex flare, and pain relief. Curr Med Res Opin, 2006. 22: 1269-76.
90. Storr, M., et al., Cannabis use provides symptom relief in patients with inflammatory bowel disease but is associated with worse disease prognosis in patients with Crohn's disease. Inflamm Bowel Dis, 2014. 20: 472-80.
91. Toth, C. and S. Au, A prospective identification of neuropathic pain in specific chronic polyneuropathy syndromes and response to pharmacological therapy. Pain, 2008. 138: 657-66.
92. Vermersch, P. and M. Trojano, Tetrahydrocannabinol: Cannabidiol oromucosal spray for multiple sclerosis-related resistant spasticity in daily practice. European Neurology, 2016. 76: 216-226.
93. Wade, D.T., et al., Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Multiple Sclerosis Journal, 2006. 12: 639-645.
94. Ware, M.A., et al., Cannabis use for chronic non-cancer pain: results of a prospective survey. Pain, 2003. 102: 211-6.
95. Weber, J., et al., Tetrahydrocannabinol (Delta 9-THC) treatment in chronic central neuropathic pain and fibromyalgia patients: Results of a multicenter survey. Anesthesiology research and practice, 2009. 2009.
96. Rudich, Z., et al., Treatment of chronic intractable neuropathic pain with dronabinol: case report of two adolescents. Pain Res Manag, 2003. 8: 221-4.
97. Higgins, J. and S. Green, Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 2011.
98. Langford, R., et al., A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis. Journal of neurology, 2013a. 260: 984-997.
99. Hagenbach, U., et al., The treatment of spasticity with [Delta] 9-tetrahydrocannabinol in persons with spinal cord injury. Spinal cord, 2007a. 45: 551.
100. Narang, S., et al., Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. The Journal of Pain, 2008a. 9: 254-264.
101. Chung, S.A., et al., Can the cannabinoid nabilone help with pain and sleep in fibromyalgia patients? Sleep, 2009a. 32: A325-A326.
102. Langford, R., et al., A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis. Journal of neurology, 2013b. 260: 984-997.
103. Ltd., G.P. A Study of Cannabis Based Medicine Extracts and Placebo in Patients With Pain Due to Spinal Cord Injury. NCT01606202 2012a [cited 2017 July 20]; Available from: https://ClinicalTrials.gov/show/NCT01606202.
104. Lynch, M.E., P. Cesar-Rittenberg, and A.G. Hohmann, A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. Journal of Pain and Symptom Management, 2014a. 47: 166-173.
105. Lynch, M.E., P. Cesar-Rittenberg, and A.G. Hohmann, A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. Journal of Pain and Symptom Management, 2014b. 47: 166-173.
106. Brady, C., et al., An open-label pilot study of cannabis-based extracts for bladder dysfunction in advanced multiple sclerosis. Multiple Sclerosis, 2004a. 10: 425-433.
107. Narang, S., et al., Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. The Journal of Pain, 2008b. 9: 254-264.
108. Hagenbach, U., et al., The treatment of spasticity with [Delta] 9-tetrahydrocannabinol in persons with spinal cord injury. Spinal cord, 2007c. 45: 551.
109. Brady, C., et al., An open-label pilot study of cannabis-based extracts for bladder dysfunction in advanced multiple sclerosis. Multiple Sclerosis, 2004b. 10: 425-433.
110. van Amerongen, G., et al., Effects on Spasticity and Neuropathic Pain of an Oral Formulation of delta9-Tetrahydrocannabinol in Patients With Progressive Multiple Sclerosis. Clinical Therapeutics., 2017a.
111. van Amerongen, G., et al., Effects on Spasticity and Neuropathic Pain of an Oral Formulation of delta9-Tetrahydrocannabinol in Patients With Progressive Multiple Sclerosis. Clinical Therapeutics., 2017b.
112. Chung, S.A., et al., Can the cannabinoid nabilone help with pain and sleep in fibromyalgia patients? Sleep, 2009b. 32: A325-A326.
113. Ware, M.A., et al., The effects of nabilone on sleep in fibromyalgia: results of a randomized controlled trial. Anesthesia & Analgesia, 2010a. 110: 604-610.
114. Pinsger, M., et al., Benefits of an add-on treatment with the synthetic cannabinomimetic nabilone on patients with chronic pain--a randomized controlled trial. Wiener Klinische Wochenschrift, 2006a. 118: 327-335.
115. Toth, C., et al., An enriched-enrolment randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain. Pain, 2012b. 153: 2073-82.
116. Palmieri, B., C. Laurino, and M. Vadalà, Short-Term Efficacy of CBD-Enriched Hemp Oil in Girls with Dysautonomic Syndrome after Human Papillomavirus Vaccination. The Israel Medical Association journal: IMAJ, 2017. 19: 79.
117. Wilsey, B., et al., An Exploratory Human Laboratory Experiment Evaluating Vaporized Cannabis in the Treatment of Neuropathic Pain From Spinal Cord Injury and Disease. Journal of Pain, 2016(i). 17: 982-1000.
118. Martinez-Rodriguez, J.E., et al., Cannabis use in Spanish patients with multiple sclerosis: fulfilment of patients' expectations? J Neurol Sci, 2008. 273: 103-7.