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Cannabis‐based medicines for chronic neuropathic pain in adults

This review is one of a series on drugs used to treat chronic neuropathic pain. Estimates of the population prevalence of chronic pain with neuropathic components range between 6% and 10%. Current pharmacological treatment options for neuropathic pain afford substantial benefit for only a few people, often with adverse effects that outweigh the benefits. There is a need to explore other treatment options, with different mechanisms of action for treatment of conditions with chronic neuropathic pain. Cannabis has been used for millennia to reduce pain. Herbal cannabis is currently strongly promoted by some patients and their advocates to treat any type of chronic pain.

Objectives

To assess the efficacy, tolerability, and safety of cannabis‐based medicines (herbal, plant‐derived, synthetic) compared to placebo or conventional drugs for conditions with chronic neuropathic pain in adults.

Search methods

In November 2017 we searched CENTRAL, MEDLINE, Embase, and two trials registries for published and ongoing trials, and examined the reference lists of reviewed articles.

Selection criteria

We selected randomised, double‐blind controlled trials of medical cannabis, plant‐derived and synthetic cannabis‐based medicines against placebo or any other active treatment of conditions with chronic neuropathic pain in adults, with a treatment duration of at least two weeks and at least 10 participants per treatment arm.

Data collection and analysis

Three review authors independently extracted data of study characteristics and outcomes of efficacy, tolerability and safety, examined issues of study quality, and assessed risk of bias. We resolved discrepancies by discussion. For efficacy, we calculated the number needed to treat for an additional beneficial outcome (NNTB) for pain relief of 30% and 50% or greater, patient’s global impression to be much or very much improved, dropout rates due to lack of efficacy, and the standardised mean differences for pain intensity, sleep problems, health‐related quality of life (HRQoL), and psychological distress. For tolerability, we calculated number needed to treat for an additional harmful outcome (NNTH) for withdrawal due to adverse events and specific adverse events, nervous system disorders and psychiatric disorders. For safety, we calculated NNTH for serious adverse events. Meta‐analysis was undertaken using a random‐effects model. We assessed the quality of evidence using GRADE and created a ‘Summary of findings’ table.

Main results

We included 16 studies with 1750 participants. The studies were 2 to 26 weeks long and compared an oromucosal spray with a plant‐derived combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) (10 studies), a synthetic cannabinoid mimicking THC (nabilone) (two studies), inhaled herbal cannabis (two studies) and plant‐derived THC (dronabinol) (two studies) against placebo (15 studies) and an analgesic (dihydrocodeine) (one study). We used the Cochrane ‘Risk of bias’ tool to assess study quality. We defined studies with zero to two unclear or high risks of bias judgements to be high‐quality studies, with three to five unclear or high risks of bias to be moderate‐quality studies, and with six to eight unclear or high risks of bias to be low‐quality studies. Study quality was low in two studies, moderate in 12 studies and high in two studies. Nine studies were at high risk of bias for study size. We rated the quality of the evidence according to GRADE as very low to moderate.

Primary outcomes

Cannabis‐based medicines may increase the number of people achieving 50% or greater pain relief compared with placebo (21% versus 17%; risk difference (RD) 0.05 (95% confidence interval (CI) 0.00 to 0.09); NNTB 20 (95% CI 11 to 100); 1001 participants, eight studies, low‐quality evidence). We rated the evidence for improvement in Patient Global Impression of Change (PGIC) with cannabis to be of very low quality (26% versus 21%;RD 0.09 (95% CI 0.01 to 0.17); NNTB 11 (95% CI 6 to 100); 1092 participants, six studies). More participants withdrew from the studies due to adverse events with cannabis‐based medicines (10% of participants) than with placebo (5% of participants) (RD 0.04 (95% CI 0.02 to 0.07); NNTH 25 (95% CI 16 to 50); 1848 participants, 13 studies, moderate‐quality evidence). We did not have enough evidence to determine if cannabis‐based medicines increase the frequency of serious adverse events compared with placebo (RD 0.01 (95% CI ‐0.01 to 0.03); 1876 participants, 13 studies, low‐quality evidence).

Secondary outcomes

Cannabis‐based medicines probably increase the number of people achieving pain relief of 30% or greater compared with placebo (39% versus 33%; RD 0.09 (95% CI 0.03 to 0.15); NNTB 11 (95% CI 7 to 33); 1586 participants, 10 studies, moderate quality evidence). Cannabis‐based medicines may increase nervous system adverse events compared with placebo (61% versus 29%; RD 0.38 (95% CI 0.18 to 0.58); NNTH 3 (95% CI 2 to 6); 1304 participants, nine studies, low‐quality evidence). Psychiatric disorders occurred in 17% of participants using cannabis‐based medicines and in 5% using placebo (RD 0.10 (95% CI 0.06 to 0.15); NNTH 10 (95% CI 7 to 16); 1314 participants, nine studies, low‐quality evidence).

We found no information about long‐term risks in the studies analysed.

Subgroup analyses

We are uncertain whether herbal cannabis reduces mean pain intensity (very low‐quality evidence). Herbal cannabis and placebo did not differ in tolerability (very low‐quality evidence).

Authors’ conclusions

The potential benefits of cannabis‐based medicine (herbal cannabis, plant‐derived or synthetic THC, THC/CBD oromucosal spray) in chronic neuropathic pain might be outweighed by their potential harms. The quality of evidence for pain relief outcomes reflects the exclusion of participants with a history of substance abuse and other significant comorbidities from the studies, together with their small sample sizes.

Plain language summary

Cannabis products for adults with chronic neuropathic pain

Bottom line

There is a lack of good evidence that any cannabis‐derived product works for any chronic neuropathic pain.

Background

Neuropathic pain is pain coming from damaged nerves. It is different from pain messages that are carried along healthy nerves from damaged tissue (for example, a fall, or cut, or arthritic knee). Neuropathic pain is treated by different medicines to those used for pain from damaged tissue.

Several products based on the cannabis plant have been suggested as treatment for pain, including neuropathic pain. These products include inhaled herbal cannabis, and various sprays or tablets containing active cannabis ingredients obtained from the plant, or made synthetically.

Some people with neuropathic pain claim that cannabis‐based products are effective for them, and that is often highlighted in the media.

Study characteristics

In November 2017 we searched for clinical trials that used cannabis products to treat conditions with chronic neuropathic pain in adults. We found 16 studies involving 1750 people. Studies lasted 2 to 26 weeks. Studies compared different cannabis‐based medicines. Ten studies compared an oromucosal (mouth) spray with a plant‐derived combination of tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, and cannabidiol (CBD), an anti‐inflammatory ingredient of cannabis, against a fake medication (placebo). Two studies each compared inhaled herbal cannabis and cannabis plant‐derived THC with placebo, and one study compared a man‐made cannabinoid mimicking the effects of THC (nabilone) with placebo. One study compared nabilone with a pain killer (dihydrocodeine).

Key results and quality of the evidence

We rated the quality of the evidence from studies using four levels: very low, low, moderate, or high. Very low‐quality evidence means that we are very uncertain about the results. High‐quality evidence means that we are very confident in the results.

There was no high‐quality evidence.

All cannabis‐based medicines pooled together were better than placebo for the outcomes substantial and moderate pain relief and global improvement. All cannabis‐based medicines pooled together were better than placebo in reducing pain intensity, sleep problems and psychological distress (very low‐ to moderate‐quality evidence).

There was no difference between all cannabis‐based medicines pooled together and placebo in improving health‐related quality of life, stopping the medication because it was not effective, and in the frequency of serious side effects (low‐quality evidence).

More people reported sleepiness, dizziness and mental problems (e.g. confusion) with all cannabis‐based medicines pooled together than with placebo (low‐quality evidence). There was moderate‐quality evidence that more people dropped out due to side effects with cannabis‐based medicines than with placebo.

Herbal cannabis was not different from placebo in reducing pain and the number of people who dropped out due to side effects (very low‐quality evidence).

Summary of findings

Background

The protocol for this review was based on a template for reviews of drugs used to relieve neuropathic pain. The aim is for all reviews to use the same methods, based on new criteria for what constitutes reliable evidence in chronic pain (Moore 2010a; Moore 2012; Appendix 1).

Description of the condition

The 2011 International Association for the Study of Pain definition of neuropathic pain is “pain caused by a lesion or disease of the somatosensory system” (Jensen 2011), and based on a definition agreed at an earlier consensus meeting (Treede 2008). Neuropathic pain is a consequence of a pathological maladaptive response of the nervous system to ‘damage’ from a wide variety of potential causes. It is characterised by pain in the absence of a noxious stimulus and may be spontaneous (continuous or paroxysmal) in its temporal characteristics or be evoked by sensory stimuli (dynamic mechanical allodynia where pain is evoked by light touch of the skin). Neuropathic pain is associated with a variety of sensory loss (numbness) and sensory gain (allodynia) clinical phenomena, the exact pattern of which vary between people and disease, perhaps reflecting different pain mechanisms operating in an individual person and, therefore, potentially predictive of response to treatment (Demant 2014; Helfert 2015; von Hehn 2012). Pre‐clinical research hypothesises a bewildering array of possible pain mechanisms that may operate in people with neuropathic pain, which largely reflect pathophysiological responses in both the central and peripheral nervous systems, including neuronal interactions with immune cells (Baron 2012; Calvo 2012; von Hehn 2012). Overall, the treatment gains in neuropathic pain, to even the most effective of available drugs, are modest (Finnerup 2015; Moore 2013a), and a robust classification of neuropathic pain is not yet available (Finnerup 2013).

Neuropathic pain is usually divided according to the cause of nerve injury. There may be many causes, but some common causes of neuropathic pain include diabetes (painful diabetic neuropathy (PDN)), shingles (postherpetic neuralgia), amputation (stump and phantom limb pain), neuropathic pain after surgery or trauma, stroke or spinal cord injury, trigeminal neuralgia, and HIV infection. Sometimes the cause is unknown.

Many people with neuropathic pain conditions are significantly disabled with moderate or severe pain for many years. Chronic pain conditions comprised five of the 11 top‐ranking conditions for years lived with disability in 2010 (Vos 2012), and are responsible for considerable loss of quality of life and employment, and increased healthcare costs (Moore 2014a). A study in the USA found that healthcare costs were three‐fold higher for people with neuropathic pain than matched control participants (Berger 2004). A UK study and a German study showed a two‐ to three‐fold higher level of use of healthcare services in people with neuropathic pain than those without (Berger 2009; Berger 2012). For postherpetic neuralgia, for example, studies demonstrate a large loss of quality of life and substantial costs (Scott 2006; Van Hoek 2009).

In systematic reviews, the overall prevalence of neuropathic pain in the general population is reported to be between 7% and 10% (Van Hecke 2014), and about 7% in a systematic review of studies published since 2000 (Moore 2014a). In individual countries, prevalence rates have been reported as 3.3% in Austria (Gustorff 2008), 6.9% in France (Bouhassira 2008), and up to 8% in the UK (Torrance 2006). Some forms of neuropathic pain, such as PDN and post‐surgical chronic pain (which is often neuropathic in origin), are increasing (Hall 2008).

Estimates of incidence vary between individual studies for particular origins of neuropathic pain, often because of small numbers of cases. In primary care in the UK, between 2002 and 2005, the incidences (per 100,000 person‐years’ observation) were 28 (95% confidence interval (CI), 27 to 30) for PHN, 27 (95% CI, 26 to 29) for trigeminal neuralgia, 0.8 (95% CI, 0.6 to 1.1) for phantom limb pain, and 21 (95% CI, 20 to 22) for PDN (Hall 2008). Other studies have estimated an incidence of 4 in 100,000 per year for trigeminal neuralgia (Katusic 1991; Rappaport 1994), and 12.6 per 100,000 person‐years for trigeminal neuralgia and 3.9 per 100,000 person‐years for PHN in a study of facial pain in the Netherlands (Koopman 2009). One systematic review of chronic pain demonstrated that some neuropathic pain conditions, such as PDN, can be more common than other neuropathic pain conditions, with prevalence rates up to 400 per 100,000 person‐years (McQuay 2007).

Neuropathic pain is difficult to treat effectively, with only a minority of people experiencing a clinically relevant benefit from any one intervention (Kalso 2013; Moore 2013b). A multidisciplinary approach is now advocated, combining pharmacological interventions with physical or cognitive (or both) interventions. The evidence for interventional management is very weak, or non‐existent (Dworkin 2013). Conventional analgesics such as paracetamol and nonsteroidal anti‐inflammatory drugs (NSAIDs) are not thought to be effective, but without evidence to support or refute that view (Moore 2015a). Some people may derive some benefit from a topical lidocaine patch or low‐concentration topical capsaicin, although evidence about benefits is uncertain (Derry 2012; Derry 2014). High‐concentration topical capsaicin may benefit some people with PHN (Derry 2017). Treatment is often by so‐called pain modulators such as antidepressants (duloxetine and amitriptyline; Lunn 2014; Moore 2017; Moore 2015b; Sultan 2008), or antiepileptics (gabapentin or pregabalin; Moore 2009; Moore 2014b; Wiffen 2013). Evidence for efficacy of opioids is unconvincing (Gaskell 2016; Sommer 2015; Stannard 2016).

The proportion of people who achieve worthwhile pain relief (typically at least 50% pain intensity reduction; Moore 2013a) is small, generally only 10% to 25% more than with placebo, with numbers needed to treat for an additional beneficial outcome (NNTB) usually between 4 and 10 (Kalso 2013; Moore 2013b). Neuropathic pain is not particularly different from other chronic pain conditions in that only a small proportion of trial participants have a good response to treatment (Moore 2013b).

The current National Institute for Health and Care Excellence (NICE) guidance for the pharmacological management of neuropathic pain suggests offering a choice of amitriptyline, duloxetine, gabapentin, or pregabalin as initial treatment for neuropathic pain (with the exception of trigeminal neuralgia), with switching if the first, second, or third drugs tried are not effective or not tolerated (NICE 2013). This concurs with other recent guidelines (Finnerup 2015).

There is a need to explore other treatment options, with different mechanisms of action and from different drug categories, for treatment of neuropathic pain syndromes. Medical cannabis has been promoted by some patient organisations and advocates for the treatment of chronic pain refractory to conventional treatment and is available for pain management in some countries of the world, e.g. Canada and Israel (Ablin 2016). However, the use of cannabis for medical reasons is highly contested because of the adverse health effects of long‐term cannabis use for recreational purposes (Volkow 2014).

Description of the intervention

The cannabinoid system is ubiquitous in the animal kingdom, with multiple functions that move the organism back to equilibrium. A large body of evidence currently supports the presence of cannabinoid (CB) receptors and ligands in the peripheral and central nervous system, but also in other tissues such as bone and in the immune system (Owens 2015).

The endocannabinoid system has three broad and overlapping functions in mammals. The first is a stress recovery role, operating in a feedback loop in which endocannabinoid signalling is activated by stress and functions to return endocrine, nervous, and behavioural systems to homeostatic balance. The second is to control energy balance through regulation of the intake, storage, and utilisation of food. The third involves immune regulation; endocannabinoid signalling is activated by tissue injury and modulates immune and inflammatory responses (Hillard 2012). Thus, the endocannabinoid neuromodulatory system appears to be involved in multiple physiological functions, such as anti‐nociception, cognition and memory, endocrine function, nausea and vomiting, inflammation, and immune recognition (De Vries 2014; Hillard 2012). Cannabis is a genus of the flowering plant in the family Cannabaceae. The number of species within the genus is disputed. Three species may be recognized, Cannabis sativa, Cannabis indica and Cannabis ruderalis. These plants, commonly known as marijuana, have been used for pain relief for millennia, and have additional effects on appetite, sleep, and mood (Kalant 2001). Data from clinical trials with synthetic and plant‐based cannabis‐based medicines suggest a promising approach for the management of chronic neuropathic pain of different origins (De Vries 2014; Jensen 2015).

How the intervention might work

Cannabis contains over 450 compounds, with at least 70 classified as phytocannabinoids. Two are of particular medical interest. Delta 9‐tetrahydrocannabinol (delta 9‐THC) is the main active constituent, with psychoactive (e.g. reduction of anxiety and stress) and pain‐relieving properties. The second molecule of interest is cannabidiol (CBD), which has lower affinity for the cannabinoid (CB) receptors and the potential to counteract the negative effects of THC on memory, mood, and cognition, but also has an effect on pain modulation by anti‐inflammatory properties. The specific roles of currently identified endocannabis‐based medicines that act as ligands at CB receptors within the nervous system (primarily but not exclusively CB 1 receptors) and in the periphery (primarily but not exclusively CB 2 receptors) are only partially elucidated, but there are abundant pre‐clinical data to support their influence on nociception (Owens 2015).

It is also hypothesised that cannabis reduces alterations in cognitive and autonomic processing in chronic pain states (Guindon 2009). The frontal‐limbic distribution of CB receptors in the brain suggests that cannabis may preferentially target the affective qualities of pain (Lee 2013). In addition, cannabis may attenuate low‐grade inflammation, another postulate for the pathogenesis of neuropathic pain (Zhang 2015).

The content of THC and CBD in medical cannabis is highly variable and ranges from 1% to 22% THC and 0.05% to 9% CBD. In contrast the THC/CBD concentration in THC/CBD (nabiximols) oromucosal spray and the THC content in plant‐derived and synthetic THC are standardised (Häuser 2017).

Taking into consideration the poorly understood pathogenesis of chronic neuropathic pain syndromes, the complexity of symptom expression, and the absence of an ideal treatment, the potential for manipulation of the cannabinoid system as a therapeutic modality is attractive.

Why it is important to do this review

While recent guidance tends to be generally in agreement about the role of antidepressants and anticonvulsants in the management of chronic neuropathic pain (Finnerup 2015; NICE 2013), the role of opioids (Sommer 2015) and of cannabis‐based medicines (Häuser 2017, Häuser 2018) is under debate. Recent systematic reviews on the use of cannabis‐based medicines to treat chronic pain came to different conclusions on their importance in chronic neuropathic pain (Boychuk 2015; Finnerup 2015; Petzke 2016; Whiting 2015). This was probably due to the inclusion of different trials, different standards to evaluate the quality of evidence, and different weighting of the outcomes of efficacy, tolerability, and safety. Due to the conflicting conclusions of recent systematic reviews on the importance of cannabis‐based medicines in treating chronic neuropathic pain, as well as the public debate on the medical use of herbal cannabis for chronic pain (Ablin 2016; Fitzcharles 2014), we saw the need for a Cochrane Review applying the standards of Cochrane Pain, Palliative and Supportive Care (PaPaS).

Objectives

To assess the efficacy, tolerability, and safety of cannabis‐based medicines (herbal, plant‐based, synthetic) compared to placebo or conventional drugs for conditions with chronic neuropathic pain in adults.

Methods

Criteria for considering studies for this review

Types of studies

We included studies if they were randomised, double‐blind, controlled trials (RCTs) of at least two weeks’ duration (drug titration and maintenance or withdrawal). We included studies with a parallel, cross‐over, and enriched enrolment randomised withdrawal (EERW) design with at least 10 participants per treatment arm. We required full journal publication, with the exception of online clinical trial results summaries of otherwise unpublished clinical trials, and abstracts with sufficient data for analysis. We did not include short abstracts. We excluded studies that were not randomised, studies of experimental pain, case reports, and clinical observations. We included studies that reported at least one outcome of efficacy and one of safety as defined below.

Types of participants

Studies included adults aged 18 years and above with one or more chronic (three months and more) neuropathic pain condition including (but not limited to):

Where included studies had participants with more than one type of neuropathic pain, we analysed results according to the primary condition. Studies had to state explicitly that they included people with neuropathic pain (by title). We excluded studies that assessed pain in people with neurological diseases without specifying that the pain assessed was of neuropathic nature. We excluded studies with fibromyalgia because the nature of fibromyalgia (neuropathic or not) is under debate (Clauw 2015); cannabis‐based medicines in fibromyalgia are the subject of another Cochrane Review (Häuser 2016). We excluded studies with ‘mixed pain’ (Baron 2004), because the concept is neither internationally accepted nor sufficiently validated and the focus of this review is only neuropathic pain.

Types of interventions

Cannabis‐based medicines, either herbal cannabis (hashish, marihuana), plant‐based cannabinoids (dronabinol: nabiximols), or pharmacological (synthetic) cannabinoids (e.g. levonantradol, nabilone), at any dose, by any route, administered for the relief of neuropathic pain and compared to placebo or any active comparator. We did not include studies with drugs under development that manipulate the endocannabinoid system by inhibiting enzymes that hydrolyse endocannabninoids and thereby boost the levels of the endogenous molecules (e.g. blockade of the catabolic enzyme fatty acid amide hydrolase (FAAH)) (Long 2009).

Types of outcome measures

The standards used to assess evidence in chronic pain trials have changed substantially in recent years, with particular attention being paid to trial duration, withdrawals, and statistical imputation following withdrawal, all of which can substantially alter estimates of efficacy. The most important change is the move from using mean pain scores, or mean change in pain scores, to the number of people who have a large decrease in pain (by at least 50%) and who continue in treatment, ideally in trials of eight to 12 weeks’ duration or longer. These standards are set out in the PaPaS Author and Referee Guidance for pain studies of Cochrane Pain, Palliative and Supportive Care (Cochrane PaPaS 2012). This Cochrane Review assessed evidence using methods that make both statistical and clinical sense, and will use criteria for what constitutes reliable evidence in chronic pain (Moore 2010a).

We anticipated that studies would use a variety of outcome measures, with most studies using standard subjective scales (numerical rating scale (NRS) or visual analogue scale (VAS) for pain intensity or pain relief, or both). We were particularly interested in Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) definitions for moderate and substantial benefit in chronic pain studies (Dworkin 2008).

Primary outcomes

Participant‐reported pain relief of 50% or greater. We preferred composite neuropathic pain scores over single‐scale generic pain scores if both measures were used by studies;

Serious adverse events (safety). Serious adverse events typically include any untoward medical occurrence or effect that at any dose results in death, is life‐threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an ‘important medical event’ that may jeopardise the person, or may require an intervention to prevent one of the above characteristics/consequences.

Secondary outcomes

Participant‐reported pain relief of 30% or greater. We preferred composite neuropathic pain scores over single‐scale generic pain scores if both measures were used by studies;

Mean pain intensity. We preferred composite neuropathic pain scores over single‐scale generic pain scores if both measures were used by studies;

Specific adverse events, particularly nervous system (e.g. dizziness, somnolence, headache) and psychiatric disorders (e.g. confusion state; paranoia, psychosis, substance dependence) according to the Medical Dictionary for Regulatory Activities (MedDRA) (International Council for Harmonisation 2016).

Search methods for identification of studies

Electronic searches

We searched the following databases, without language restrictions:

The Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO) (searched 7 November 2017);

Appendix 2 shows the search strategies.

Searching other resources

We reviewed the bibliographies of any RCTs identified and review articles, and searched the following clinical trials databases: US National Institutes of Health clinical trial register (www.ClinicalTrials.gov), European Union Clinical Trials Register (www.clinicaltrialsregister.eu), World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/), and International Association for Cannabinoid Medicines (IACM) databank (www.cannabis-med.org/studies/study.php) to identify additional published or unpublished data. We contacted trial investigators to request missing data.

Data collection and analysis

We performed separate analyses according to particular neuropathic pain conditions. We combined different neuropathic pain conditions in analyses for exploratory purposes only.

Selection of studies

Two review authors (WH, FP) determined eligibility by reading the abstract of each study identified by the search. We eliminated studies that clearly did not satisfy the inclusion criteria, and obtained full copies of the remaining studies. Two review authors (WH, FP) independently read these studies and reached agreement by discussion. We did not anonymise the studies before assessment. We created a PRISMA flow chart (Moher 2009).

Data extraction and management

Two review authors (WH, FP) extracted data independently using a standard form and checked for agreement before entering data into Review Manager 5 (RevMan 2014). Two review authors (WH, MM) extracted independently data calculated by imputation. We included information about the pain condition and number of participants treated, study setting, inclusion and exclusion criteria, demographic and clinical characteristics of the study samples (age, gender, race, pain baseline), prior recreational cannabis use, drug and dosing regimen, co‐therapies allowed, rescue medication, study design (placebo or active control), study duration and follow‐up, analgesic outcome measures and results, withdrawals, and adverse events (participants experiencing any adverse event or serious adverse event).

Assessment of risk of bias in included studies

Two review authors (WH, FP) independently assessed risk of bias for each study, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a), and adapted from those used by Cochrane Musculoskeletal for recent reviews on drug therapy in fibromyalgia, with any disagreements resolved by discussion. We assessed the following for each study.

Random sequence generation (checking for possible selection bias). We assessed the method used to generate the allocation sequence as: low risk of bias (i.e. any truly random process, e.g. random number table; computer random number generator); unclear risk of bias (when the method used to generate the sequence was not clearly stated). We excluded studies at a high risk of bias that used a non‐random process (e.g. odd or even date of birth; hospital or clinic record number).

Allocation concealment (checking for possible selection bias). The method used to conceal allocation to interventions prior to assignment determines whether intervention allocation could have been foreseen in advance of, or during, recruitment, or changed after assignment. We assessed the methods as: low risk of bias (e.g. telephone or central randomisation; consecutively numbered, sealed, opaque envelopes); unclear risk of bias (when method was not clearly stated). We excluded studies that did not conceal allocation and were therefore at a high risk of bias (e.g. open list).

Blinding of participants and personnel/treatment providers (systematic performance bias). We assessed the methods used to blind participants and personnel/treatment providers from knowledge of which intervention a participant received. We assessed the methods as: low risk of bias (study stated that it was blinded and described the method used to achieve blinding, e.g. identical tablets; matched in appearance and smell); unclear risk of bias (study stated that it was blinded but did not provide an adequate description of how it was achieved); high risk of bias (blinding of participants was not ensured, e.g. tablets different in form or taste).

Blinding of outcome assessment (checking for possible detection bias). We assessed the methods used to blind study outcome assessors from knowledge of which intervention a participant received. We assessed the methods as: low risk of bias (study stated that outcome assessors were blinded to the intervention or exposure status of participants); unclear risk of bias (study stated that the outcome assessors were blinded but did not provide an adequate description of how it was achieved); high risk of bias (outcome assessors knew the intervention or exposure status of participants).

Incomplete outcome data (checking for possible attrition bias due to the amount, nature, and handling of incomplete outcome data). We assessed the methods used to deal with incomplete data as: low risk of bias (i.e. less than 10% of participants did not complete the study or used ‘baseline observation carried forward’ (BOCF) analysis, or both); unclear risk of bias (used ‘last observation carried forward’ analysis); or high risk of bias (used ‘completer’ analysis).

Reporting bias due to selective outcome reporting (reporting bias). We checked if an a priori study protocol was available and if all outcomes of the study protocol were reported in the publications of the study. There is low risk of reporting bias if the study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review are reported in the pre‐specified way, or if the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that are pre‐specified (convincing text of this nature may be uncommon). There is a high risk of reporting bias if not all of the study’s pre‐specified primary outcomes are reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that are not pre‐specified; one or more reported primary outcomes are not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; the study report did not include results for a key outcome that would be expected to have been reported for such a study. There is unclear risk of bias if insufficient information is available to permit judgement of ‘Low risk’ or ‘High risk’.

Group similarity at baseline (selection bias). We assessed similarity of the study groups at baseline for the most important prognostic clinical and demographic indicators. There is low risk of bias if groups are similar at baseline for demographic factors, value of main outcome measure(s), and important prognostic factors. There is an unclear risk of bias if important prognostic clinical and demographic indicators are not reported. There is high risk of bias if groups are not similar at baseline for demographic factors, value of main outcome measure(s), and important prognostic factors.

Size of study (checking for possible biases confounded by small size). We assessed studies as being at low risk of bias (200 participants or more per treatment arm); unclear risk of bias (50 to 199 participants per treatment arm); or high risk of bias (fewer than 50 participants per treatment arm).

Two review authors (WH, FP) assessed the included studies using the Cochrane ‘Risk of bias’ tool. We defined studies with zero to two unclear or high risks of bias to be high‐quality studies, with three to five unclear or high risks of bias to be moderate‐quality studies, and with six to eight unclear or high risks of bias to be low‐quality studies (Schaefert 2015).

Measures of treatment effect

We calculated numbers needed to treat for an additional beneficial outcome (NNTB) as the reciprocal of the absolute risk reduction (ARR; McQuay 1998). For unwanted effects, the NNTB becomes the number needed to treat for an additional harmful outcome (NNTH) and is calculated in the same manner. We used dichotomous data to calculate risk differences (RD) with 95% CIs using a fixed‐effect model unless we found significant statistical or clinical heterogeneity (see below). We set the threshold for a clinically relevant benefit or a clinically relevant harm for categorical variables by an NNTB or NNTH less than 10 (Moore 2008).

We calculated standardised mean differences (SMD) with 95% CIs for continuous variables using a fixed‐effect model unless we found significant statistical or clinical heterogeneity. We used Cohen’s categories to evaluate the magnitude of the effect size, calculated by SMD, with Hedges’ g value of 0.2 = small, 0.5 = medium, and 0.8 = large (Cohen 1988). We labelled a g value less than 0.2 to be a ‘not substantial’ effect size. We assumed a minimally important difference if the Hedges’ g value was 0.2 or greater (Fayers 2014).

Unit of analysis issues

We split the control treatment arm between active treatment arms in a single study if the active treatment arms were not combined for analysis.

We included studies with a cross‐over design where separate data from the two periods were reported, data were presented that excluded a statistically significant carry‐over effect, or statistical adjustments were carried out in case of a significant carry‐over effect.

Dealing with missing data

We used intention‐to‐treat (ITT) analysis where the ITT population consisted of participants who were randomised, took at least one dose of the assigned study medication, and provided at least one post‐baseline assessment.

Where means or standard deviations (SDs) were missing, we attempted to obtain these data through contacting trial authors. Where SDs were not available from trial authors, we calculated them from t values, P values, CIs, or standard errors, where reported by the studies (Higgins 2011b). Where rates of pain relief of 30% and of 50% or greater were not reported or provided on request, we calculated them from means and SDs using a validated imputation method (Furukawa 2005).

Assessment of heterogeneity

We dealt with clinical heterogeneity by combining studies that examined similar conditions. We assessed statistical heterogeneity visually (L’Abbé 1987), and using the I 2 statistic (Higgins 2003). When the I 2 value was greater than 50%, we considered possible reasons for this.

Assessment of reporting biases

We assessed publication bias using a method designed to detect the amount of unpublished data with a null effect required to make any result clinically irrelevant (usually taken to mean an NNTB of 10 or higher; Moore 2008).

Data synthesis

We intended to use a fixed‐effect model for meta‐analysis. We used a random‐effects model using the inverse variance method in Review Manager 5 for meta‐analysis (RevMan 2014) because there was significant clinical heterogeneity due to the different types of neuropathic pain conditions included.

Quality of the evidence

Two review authors (WH, FP) independently rated the quality of the outcomes. We used the GRADE system to rank the quality of the evidence using the GRADEpro Guideline Development Tool software (GRADEpro GDT 2015), and the guidelines provided in Chapter 12.2 of the CochraneHandbook for Systematic Reviews of Interventions (Schünemann 2011).

The GRADE approach uses five considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence for each outcome. The GRADE system uses the following criteria for assigning grade of evidence:

moderate: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different;

low: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect;

very low: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

We decreased the grade rating by one (‐ 1) or two (‐ 2) if we identified:

In addition, there may be circumstances where the overall rating for a particular outcome needs to be adjusted as recommended by GRADE guidelines (Guyatt 2013a). For example, if there are so few data that the results are highly susceptible to the random play of chance, or if a study uses last observation carried forward (LOCF) imputation in circumstances where there are substantial differences in adverse event withdrawals, one would have no confidence in the result, and would need to downgrade the quality of the evidence by three levels, to very low quality. In circumstances where there were no data reported for an outcome, we planned to report the level of evidence as very low quality (Guyatt 2013b).

See also Appendix 3: GRADE: criteria for assigning grade of evidence.

‘Summary of findings’ table

We included one ‘Summary of findings’ table to present the main findings in a transparent and simple tabular format. In particular, we included key information concerning the quality of evidence, the magnitude of effect of the interventions examined, and the sum of available data on the outcomes. The ‘Summary of findings’ table includes the primary outcomes and the secondary outcomes of participant‐reported pain relief of 30% or greater, and nervous system disorders and psychiatric disorders as specific adverse events.

Subgroup analysis and investigation of heterogeneity

We performed subgroup analyses according to individual neuropathic pain syndromes because placebo response rates for the same outcome can vary between conditions, as can the drug‐specific effects (Moore 2013b). We performed subgroup analyses (different cannabis‐based medicines; very short‐term (less than four weeks), short‐term (four to 12 weeks), intermediate‐term (13 to 26 weeks), and long‐term (more than 26 weeks) study duration) where there were at least two studies available. We post‐hoc decided to perform subgroup analyses of studies with and without publication in peer‐reviewed journals. We performed subgroup analyses if at least two studies for a subgroup were available.

Sensitivity analysis

We planned no sensitivity analysis because the evidence base is known to be too small to allow reliable analysis.

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Safety of Medical Cannabis in Neuropathic Chronic Pain Management

1 Operative Unit and School of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; [email protected] (A.B.); [email protected] (S.G.); [email protected] (D.G.S.)

Carmen Mannucci

2 Department of Biomedical and Dental Sciences and Morphological and Functional Imaging, University of Messina, 98125 Messina, Italy; [email protected]

Fabrizio Calapai

3 Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98125 Messina, Italy; [email protected]

Luigi Cardia

4 Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; [email protected] (L.C.); [email protected] (I.A.)

Ilaria Ammendolia

4 Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; [email protected] (L.C.); [email protected] (I.A.)

Sebastiano Gangemi

1 Operative Unit and School of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; [email protected] (A.B.); [email protected] (S.G.); [email protected] (D.G.S.)

Gioacchino Calapai

2 Department of Biomedical and Dental Sciences and Morphological and Functional Imaging, University of Messina, 98125 Messina, Italy; [email protected]

Daniel Griscti Soler

1 Operative Unit and School of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; [email protected] (A.B.); [email protected] (S.G.); [email protected] (D.G.S.)

1 Operative Unit and School of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; [email protected] (A.B.); [email protected] (S.G.); [email protected] (D.G.S.)

2 Department of Biomedical and Dental Sciences and Morphological and Functional Imaging, University of Messina, 98125 Messina, Italy; [email protected]

3 Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98125 Messina, Italy; [email protected]

4 Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; [email protected] (L.C.); [email protected] (I.A.)

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Abstract

Products derived from the plant Cannabis sativa are widely appreciated for their analgesic properties and are employed for the treatment of chronic neuropathic pain. Only nabiximols, a product composed of two extracts containing similar percentages of the two cannabinoids cannabidiol and delta-9-tetrahydrocannabinol, is approved by regulatory authorities for neuropathic pain and spasticity due to multiple sclerosis in many European countries and Canada. It is also included in pharmacovigilance systems monitoring the occurrence of adverse drug reactions. However, it is not the same for the great variety of other cannabis preparations widely used for medical purposes. This creates a situation characterized by insufficient knowledge of the safety of cannabis preparations and the impossibility of establishing a correct risk–benefit profile for their medical use in the treatment of chronic neuropathic pain. With the aim to explore this issue more deeply, we collected data on adverse reactions from published clinical studies reporting the use of cannabis for neuropathic relief.

1. Introduction

Chronic pain is a common condition characterized by pain that lasts 12 weeks or more. One in five adults in Europe, or 75 million people, suffer moderate to severe pain [1]. There are three main types of pain: neuropathic, nociceptive, and nociplastic. Nociceptive pain derives from activity in neural pathways, secondary to actual tissue damage or potentially tissue-damaging stimuli. Neuropathic pain originates from lesions or dysfunction of the central or peripheral nervous system [2]. Nociplastic pain arises from altered nociception, despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors, or no evidence of disease or lesion of the somatosensory system causing the pain [3].

The plant Cannabis sativa has been appreciated for its medicinal properties, and its medical use in Asia dates back to ancient times. Over the centuries, however, there was dwindling interest in the health benefits of cannabis, which was renewed in the 1990s with the description of cannabinoid (CB) receptors and the identification of the endogenous cannabinoid system [4]. Cannabis sativa has more than 60 oxygen-containing aromatic hydrocarbon compounds, known as cannabinoids. Most of their effects seem to be mediated through cannabinoid receptors, two types of which have been isolated and cloned, CB1 and CB2. CB1 receptors are distributed widely in the nervous system and seems to have a general role in the inhibition of neurotransmitter release, whereas CB2 receptors are mainly found on cells of the immune system [5]. The most known cannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC acts as a psychotomimetic agent and is responsible for most of the adverse effects (AEs) associated with the use of cannabis. CBD is not psychotomimetic, while it seems to counteract the negative effects of THC [6]. A very high binding affinity of THC with the CB1 receptor appears to mediate its effects. CBD has little binding affinity for either CB1 or CB2 receptors, but is capable of antagonizing them in the presence of THC. In fact, CBD behaves as a non-competitive negative allosteric modulator of CB1 receptor and reduces the efficacy and potency of THC [7].

Neuropathic pain (NP) is typically characterized by positive (gain of somatosensory function) and negative (loss of somatosensory function) sensory symptoms and signs [8]. Chronic NP can develop from either peripheral or central NP conditions. The International Association for the Study of Pain (IASP) published its latest classification of NP; the subtypes of chronic peripheral NP are as follows: trigeminal neuralgia (TN), chronic NP after peripheral nerve injury, painful polyneuropathy, post-herpetic neuralgia, and painful radiculopathy. Chronic central NP subtypes include chronic central NP associated with spinal cord injury (SCI) or brain injury, chronic central post-stroke pain, and chronic central NP associated with multiple sclerosis (MS) [9]. There is no single diagnostic test or pathognomonic symptom to identify NP; hence, clinical acumen is required. In this light, neuropathic screening tools have been developed as diagnostic aids, including the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), the Neuropathic Pain Questionnaire (NPQ), Douleur Neuropathique 4 Questions, and painDETECT [10]. Nabiximols (marketed as Sativex), composed of two extracts containing similar parts of CBD and THC extracts, is a cannabis-derived drug approved for neuropathic pain and spasticity due to multiple sclerosis in many European countries and Canada [11]. Authorized by regulatory agencies in different countries, Sativex is included in pharmacovigilance systems monitoring the occurrence of adverse drug reactions. The regulations are not the same for the great variety of cannabis preparations widely used for medical purposes, which has led to a situation where there is insufficient knowledge of the safety of cannabis and it is impossible to establish a correct risk/benefit profile for its medical use. Cannabis preparations that are not licensed as drugs are mostly used for pain [12].

It has been observed that plant-derived cannabinoids act on different pain targets. Together with their activity on cannabinoid receptors, on which THC action is prevalent, these substances exert their analgesic effects by interacting with G protein-coupled receptor (GPCR) 55 and other pharmacological targets, such as opioid and serotonin receptors [13,14]. CBD is also considered an inverse agonist to GPR3, GPR6, and GPR12 receptors, which are involved in the occurrence of neuropathic pain [15]. The analgesic effects of THC and CBD have been associated with the potentiation of α3 glycine receptors, which are widely diffused in the spinal cord dorsal horn and act as modulators of inflammatory pain [16].

With the aim of gaining an overview of the safety of cannabis use for NP relief, we selected published scientific articles describing results on efficacy and reporting the frequency and severity of adverse reactions to cannabis preparations administered for this medical purpose.

2. Methodology

Bibliographic research was carried out independently by two researchers (blinded to the authors) in major scientific databases (PubMed, Scopus, and Google Scholar) and a search engine of peer-reviewed literature on life sciences and biomedical topics. The investigators used the keywords “cannabis” and “pain” alone and in combination. All articles written in the English language and published in peer-reviewed scientific journals describing clinical trials and applications of cannabis extracts (CE) in oral or inhaled form for chronic neuropathic pain relief were collected and discussed. According to the PRISMA statement, PICOS (population, intervention, comparison, outcome) elements that formed the basis of this are showed in the Table 1 .

Table 1

PICOS (population, intervention, comparison, outcome, setting) criteria for inclusion of studies.

Parameter Inclusion Criteria
Population Adults (≥18 years old) with chronic neuropathic pain
Intervention Cannabis derived products
Comparison Placebo or any other
Outcome Improvement of pain releaf and safety of treatment
Setting Randomized and non-randomized clinical trials

The following types of scientific articles were excluded: case series, case reports, and animal studies; publications that made no reference to AEs; publications not written in the English language; studies investigating only THC or CBD individually; studies carried out using nabiximols or oromucosal/sublingual spray preparations; studies based on oncological patients; studies using co-administration of cannabis and opioids; and studies based on recreational cannabis use ( Figure 1 ).

Flow chart of total records identified through database searching (n = 388).

3. Results

A total of 15 articles corresponding to the same number of studies met our research criteria: 9 randomized double-blind placebo-controlled crossover studies, 3 randomized placebo-controlled trials, 1 prospective non-randomized single-arm clinical trial, 1 prospective cohort study with one year follow-up, and 1 single-dose open-label study ( Figure 1 ). Their principal characteristics are reported in Table 2 .

Table 2

Principal characteristics of clinical studies reporting the use of Cannabis for neuropathic relief.

Vaporized Administration
Reference Indication Study Design and No. of Patients (pts). Period of Treatment Dose Mode of Adminastration Adverse Effects(AEs) Serious Adverse Effects (SAEs) Outcome
Van de Donk et al., 2019 [17] Fibromyalgia Randomized placebo-controlled 4-way crossover trial
25 pts
4 days THC 22%/CBD < 1%
T.D. 13.4 mg/1 mg, THC 6.3%/CBD 8% T.D.
THC 13.4 mg/CBD 17.4 mg
THC < 1%/CBD 9%
T.D. 1 mg/18.4 mg
Placebo
Vp Sore throat, bad taste, nausea (1/3 of pts). Cough (2/3 of pts). No Increase in pressure pain threshold.
No analgesic effect.
Wilsey et al., 2016
[22]
Spinal cord trauma or disease Randomized, double-blind, placebo-controlled, crossover design study
42 pts
3 days THC 2.9%, THC 6.7%,
placebo minimum dose:
400 mg of cannabis.
Vp H.D.: hungry ad memory disorders with more intensity than L.D.
L.D.: high, stoned, sedated, changes in perceiving space, confused, minor attention.
No withdrawal
No Reduction in pain intensity. No significant difference in pain relief between the higher and lower dose
Wallace et al., 2015
[20]
Diabetic neuropathy Randomized, double-blinded, placebo controlled crossover study
16 pts
4 days THC 1%, 4%, 7% or placebo
Each dose: 400 mg of cannabis
Vp Euphoria with H.D. and M.D.
Somnolence
with the high dose group.
No withdrawals
No Dose-dependent reduction in the intensity of spontaneous and evoked pain.
Eisenberg et al., 2014
[21]
Complex Regional Pain Syndrome, radiculopathy, pelvic neuropathic pain, Spinal cord injury Single-dose, open-label design
8 pts
1 day THC 19.9%/CBD 0.1% CBN 0.2%;
single dose: 15.1 mg ± 0.1 mg of cannabis flos
Vp Lightheadedness
No withdrawals
No Effective for heterogeneous collection of neuropathic pain conditions studied.
Wilsey et al., 2013
[25]
P.N.P.: CRPS type I, diabetic neuropathy, idiopathic peripheral neuropathy, post-herpetic neuralgia, brachial plexopathy, radiculopathy.
C.N.P.: spinal cord injury, Multiple Sclerosis, thalamic pain
Double-blind, placebo-controlled, crossover study
39 pts
3 days L.D. THC (1.29%), M.D. THC (3.53%), or placebo
Cannabis dose = 0.8 g of per administration.
Vp M.D. high, stoned, sedation.
Reduction of learning and memory. Light reduction during testing of psychomotor skills with the dominant hand.
No withdrawals
No Analgesic efficacy with L.D. and M.D.
Smoked Admistration
Reference Indication Design of the Study and No. of pts. Period of Treatment Dose Mode of Administration Adverse Effects
(AEs)
Serious Adverse Effects (SAEs) Outcome
Corey-Bloom et al., 2012
[24]
Multiple Sclerosis Randomized, double-blind, placebo controlled crossover design
37 pts
2 days THC 4% or placebo S High, dizziness and fatigue.
5 participants withdrew.
No Beneficial effects for spasticity and pain associated with multiple sclerosis.
Ware et al., 2010
[26]
Post-traumatic or post-surgical neuropathic pain Randomized, double-blind, placebo-controlled, four period crossover design
23 pts
20 days THC 2.5%, 6.0%, and 9.4% or placebo.
Single 25-mg dose three times daily
for the first five days in each cycle
S H.D.: headache, dry eyes, burning sensation, dizziness, numbness and cough. No Reduction of pain intensity. Improvement of sleep, anxiety and depression.
Ellis et al., 2009
[27]
HIV-associated distal sensory predominant polyneuropathy (DSPN) A phase II, single group, double-blind, placebo-controlled, crossover trial
34 pts
10 days THC 1–8% or placebo
Three times daily
S Concentration difficulties, fatigue, sleepiness or sedation, increased duration of sleep, reduced salivation, thirst, increased heart rate Induction of psychosis. Intractable cough.
2 participants were withdrawn for safety reasons.
Reduction of neuropathic pain intensity in HIV-associated DSPN
Wilsey et al., 2008
[28]
Complex regional pain syndrome type I, spinal cord injury, multiple
sclerosis, peripheral neuropathy
Randomized, double-blinded, placebo-controlled, crossover design
38 pts
3 days THC 7%, THC 3.5% or placebo S H.D.: impairment in attention, learning and memory, and psychomotor speed.
L.D. 3.5%: decline in learning and memory.
No withdrawals
No Reduction of pain intensity.
No differences were observed with the two doses.
Abrams et
al., 2007
[29]
HIV-associated sensory neuropathy Prospective randomized placebo-controlled trial
55 pts
12 days THC 3.56% or placebo three times daily. S Anxiety, sedation, disorientation, paranoia, confusion, dizziness, nausea.
No withdrawals
No Relief of chronic neuropathic pain.
Oral Adminstration
Reference Indication Design of the Study and No. of pts. Period of Treatment Dose Mode of Administration Adverse Effects
(AEs)
Serious Adverse Effects (SAEs) Outcome
Poli et al., 2018
[18]
FM, radiculopathy, headache, arthritis, various form of neuropathic pain and other chronic pain conditions Prospective non-randomized single-arm clinical trial
338 pts
12 months THC 19%, CBD < 1%. Starting dose 5 mg/d of THC; at 6 months dose was 10 mg/d. D Sleepiness and mental confusion. No Reduced pain intensity. Reduction in anxiety and depression.
Zajicek et al.,
2012
[23]
Multiple Sclerosis (MUSEC trial) Double blind, placebo controlled, phase III study
277 pts
12 weeks THC 5–25 mg or placebo daily C Dizziness, disturbance in attention, balance disorder, somnolence, dry mouth, nausea, diarrhea, fatigue, urinary infection, disorientation.
Cannabis: thirty pts withdrew due to AEs.
Urinary tract infections, head injury, and interstitial lung disease. Reduction of muscle stiffness
Zajicek et al.,
2003
[30]
Multiple sclerosis (CAMS study) Randomised, placebo-controlled trial
630 pts
15 weeks 2.5 mg synthetic THC,
2.5 mg THC + 1.25 mg CBD,
placebo.
Max 25 mg THC daily
C Dizziness, dry mouth, diarrhoea in active groups.
Cannabis: constipation.
One pt died from pneumonia after 13 weeks in the THC group. Some improvement in mobility as assessed by patients indicates a subjective clinical effect.
Killestein et al., 2002
[31]
Multiple Sclerosis Randomized, double-blind, placebocontrolled, twofold crossover
study
16 pts
12 weeks THC,
THC + 20–30% CBD,
placebo.
THC 2.5 mg twice daily for first two weeks, then dose was increased to 5 mg twice daily.
C Dry mouth, headache, dizziness, increased, spasticity, somnolence, ataxia, dry mouth, emotional lability
No withdrawals
Acute psychosis episode in one pt. Results do not suggest therapeutic benefit of either THC or
plant-extract treatment.
Vaporized, Smoking, and Oral Administration
Reference Indication Design of the Study and No. of pts. Period of Treatment Dose Mode of Administration Adverse Effects
(AEs)
Serious Adverse Effects (SAEs) Outcome
Ware et al., 2015
[19]
Chronic non-cancer pain Randomized, double-blind, placebo-controlled, four period crossover design
431 pts
12 months THC 12.5 ± 1.5% or placebo.
Median daily dose cannabis = 2.5 g/d.
S, C, and Vp THC: headache, dry eyes, burning sensation, dizziness, numbness, cough.
Cannabis: 10 pts withdrew due to AEs and 5 due to AEs and lack of efficacy.
Not statistically significant Cannabis users: a mean 50 mL decrease in FEV1 and a mean 1% decrease in the FEV1/FVC ratio over 1 year.

THC = Tetrahydrocannabinol; CBD = cannabidiol; CBN: Cannabinol; Vp = vaporization; S = smoke; D = decoction; C = capsules; T.D. = total dose; H.D. = high dose; M.D. = medium dose; L.D. = low dose.

In the Netherlands, an experimental randomized placebo-controlled four-way crossover trial recruited 20 patients with chronic fibromyalgia pain and analyzed the analgesic effects of inhaled therapeutic cannabis. In the study, 100 mg each of three cannabis strains—Bedrocan (22.4 mg THC, 1 mg CBD), Bediol (13.4 mg THC, 17.8 mg CBD), and Bedrolite (18.4 mg CBD, 1 mg THC)—and placebo were given in a single day. There was no difference between the effects of active treatment and placebo on spontaneous pain evoked by electrical stimuli. Indeed, Bedrocan and Bediol caused a significant increase in the tolerance to pressure pain threshold. The most relevant effect was observed for the cannabis strain that contained high doses of THC and CBD (Bediol). When CBD was given with a very small dose of THC (Bedrolite, which mainly contains CBD), the analgesic effects were not superior to placebo. This result differs from those of studies in which patients with chronic pain reported beneficial effects with CBD treatment, probably related to improved anxiety, insomnia, and mood. Perhaps a single dose was insufficient to determine the analgesic effect or the dose was too low. With reference to adverse events, all three active treatments were associated with AEs related to the inhalation of cannabis, and the most common were drug high, dizziness, and nausea. There were no differences in the frequency of adverse events [17].

In Italy in 2018, a prospective non-randomized single-arm clinical trial analyzed data from 338 patients with fibromyalgia, headache, radiculopathy, and various forms of neuropathic pain. They received a daily dose of 5–40 mg/day of THC (many of the participants required 10 mg/day) as a decoction, corresponding to 28–210 mg of cannabis flos with 19% THC and 1% CBD for 12 months, and the intensity of pain was evaluated at follow-up visits. Among the patients, 33 stopped the study due to AEs, possibly due to the high percentage of THC in Bedrocan (19%), and 77 patients the study due to little benefit. The appearance of AEs was greater in the cannabis treatment groups than in the control, but they were transitory because they regressed after being interrupted. The most frequent were drowsiness and mental confusion, and other non-serious adverse events after termination of the study were worsening tachycardia, itching, diarrhea, gastralgia, nausea and vomiting, anal burning, increased depression, increased appetite, hallucinations, and muscle weakness. This study showed that treatment with cannabis is effective in reducing the intensity of pain, as measured by a visual analogue scale (VAS), and the disability caused by chronic pain as well as the resulting anxiety and depression, via the Hospital Anxiety and Depression Scale (HADS), without generating severe adverse events [18].

The safety profile of cannabis in the management of chronic non-cancerous pain was studied in a prospective cohort study, the Compass study. A 12.5% THC cannabis extract (CE) was dispensed with cannabis smoke to 215 subjects, in most cases for one year, with 216 nonsmoking subjects considered as a control group. The main outcome was the occurrence of serious adverse events (SAEs) and non-SAEs. The daily median dose was 2.5 g/d, and the recommended maximum limit was 5 g/d. No difference in the risk of SAEs between the two groups was detected, but in the cannabis group there was an increased risk of mild to moderate reactions, especially related to the nervous and psychiatric systems. The cannabis group was composed of 66% current cannabis users, 27% former cannabis users, and 6% cannabis naive users. The control group included 32% former cannabis users and 68% naive cannabis users. The most common SAEs in the cannabis group were abdominal pain, intestinal obstruction, and nephrolithiasis. However, none of the SAEs were definitely or likely related to cannabis. Two patients stopped the study due to SAEs, one with seizures considered possibly related to cannabis use and one for alcohol problems. Headache, nasopharyngitis, nausea, drowsiness, and dizziness were the most common non-SAEs reported. The cannabis group had also a higher rate of developing mild respiratory adverse events during the 12 months than the control group. In the study, the authors pointed out that cannabis users had an average decrease in FEV1 of 50 mL and an average reduction of 1% of the FEV1/FVC ratio after one year. As a secondary outcome, there was significant improvement in pain intensity and quality of life after one year for the cannabis group compared to control. In conclusion, the results of this study suggest that the adverse events with cannabis for medical use are modest and that an average dose of 2.5 g/d can be included in pain management programs safely with careful monitoring if conventional treatments have been considered inappropriate or inadequate [19].

The efficacy and tolerability of inhaled cannabis was investigated in a short-term randomized double-blind control study conducted on 16 patients with pain caused by diabetic neuropathy. Each patient was exposed to four single doses of aerosolized placebo or a low dose (1% THC), medium dose (4% THC), or high dose (7% THC) of cannabis with 1% CBD. Baseline values were collected for basic spontaneous pain, evoked pain, and cognitive tests. Pain intensity and cognitive capacity were measured for 4 h. The weight of 400 mg of plant material for administration corresponded to 0, 4, 16, or 28 mg THC per dosing session. Each participant received a placebo or a cannabis dose with 1, 4, or 7% THC with an interval of 2 weeks between doses. Adverse events were feelings of euphoria and drowsiness, significantly relevant at high and medium doses compared to placebo. This study found a dose-dependent reduction in the intensity of spontaneous and evoked pain in response to cannabis inhalation in patients with diabetic neuropathy. There were significant differences in the levels of spontaneous pain between placebo and active doses (low, medium, and high doses) and between the high dose and the other active doses. There was also impaired performance on neuropsychological tests with the high dose [20].

An Israeli study in 2014 aimed to examine the pharmacokinetics, safety, tolerability, efficacy, and ease of use of a new portable thermal dose inhaler (tMDI) for cannabis by analyzing a cohort of eight patients suffering from neuropathic pain who were on a stable analgesic regime that included medicinal cannabis. Four had complex regional pain syndrome (CRPS), two had lumbosacral radiculopathy, one had pelvic neuropathic pain, and one had pain related to spinal cord injury. Patients received a single dose of 15.1 ± 0.1 mg of cannabis through the inhaler device. A blood sample was taken to evaluate delta-9-THC and 11-hydroxy-9 THC at baseline and 120 min after inhalation of cannabis. The drug used was cannabis flos (Bedrocan) containing 19.9% THC, 0.1% CBD, and 0.2% CBN. All patients were treated with inhaled cannabis by smoking 2 or 3 times a day. The monthly median dose used was 20–30 mg. In this study, the low dose of THC produced an analgesic effect on the various conditions that caused neuropathic pain. A single inhalation containing 3.08 ± 0.02 mg of THC raised the plasma level of delta-9-THC Cmax to 38 ± 10 ng/mL and provided a 45% reduction in pain intensity [21].

In a study published in 2016 in the USA, 42 participants with neuropathic pain caused by injury or spinal cord disease were recruited, and the analgesic efficacy of 400 mg cannabis administered via the Volcano vaporizer was assessed using placebo and doses of 2.9% or 6.5% THC (11.6 mg and 26.8 mg THC, respectively). The study was carried out in three 8 h sessions with a median interval of about 7 days between sessions. The patients’ pathologies included multiple sclerosis, cervical disc pathology, spinal cord cancer, occlusion of the vertebral artery, arachnoid cysts, and syringomyelia. Among the patients, 90% had previously used cannabis.

During the session, participants inhaled 4 puffs of cannabis or placebo, and 240 min later were asked to choose a dose ranging from 4 to 8 puffs. Prior to placebo administration, there was no significant difference in the pain rate between placebo and 2.9% and 6.7% THC doses. Then there was a significant dose effect on pain intensity. The post hoc Tukey test showed a step-by-step effect with the highest pain intensity in the placebo group and the lowest in the higher THC group. Recent cannabis did not affect the results. One hour after the first treatment dose and one hour after the variable phase, both active doses were associated with significantly lower pain than placebo. Pain relief persisted for another 2 h from the variable dose, but the impact on pain showed no distinction between upper and lower doses of THC. Both active doses did not affect allodynia, which is consistent with the lack of benefit of cannabinoid treatment in postoperative pain. Many of the psychoactive side effects were concentration-dependent. The highest THC doses have been associated with significantly higher levels of “desires”, appetite, difficulty remembering things, drunkenness, and confusion [22].

A phase III multicenter clinical trial was designed to investigate a standardized oral CE used for the symptomatic relief of muscle stiffness and pain in 277 adult patients with stable MS treated with CE or placebo twice daily for 12 weeks (2 weeks titration phase, 10 weeks maintenance phase). The active treatment was an extract from Cannabis sativa in soft gelatin capsules containing 2.5 mg THC and 0.8–1.8 mg CBD. Subsequent doses were individually titrated upward by 5 mg THC/day every 3 days up to 12 days to optimize the ratio between therapeutic effect and side effects, and to achieve a maximum daily dose of 25 mg THC. The primary outcome was based on an 11-point category rating score (CRS) measuring perceived changes in muscle stiffness and perceived relief from body pain, muscle spasms, and sleep disturbance as a secondary outcome.

Patients treated with cannabis were divided into groups based on the severity of their symptoms of muscle stiffness and pain (low vs. high) and use of drugs (yes or no) to fight muscle spasms and pain. The level of relief, as reported by patients, was higher in the group treated with cannabis, detected after 4, 8, and 12 weeks, with the greatest difference observed in those not using antispastic drugs (37.9% cannabis vs. 16.3% placebo). When the titration period was completed, 87% of patients in the placebo group and 47% in the cannabis group took the maximum dose of 25 mg every day, and the percentages were lower at the end of the treatment period (24.5% vs. 69.4%). In the cannabis group, 33 subjects (21%) and 9 patients (6.7%) were withdrawn from or suspended treatment because of AEs. About 95% of AEs detected in all treatment groups were mild or moderate and transitory, and were not present at the end of the treatment period. SAEs were reported by 7 patients (3 patients reported urinary infections) in the cannabis group (4.9%) and 3 patients in the placebo group (2.2%). The rate of AEs was higher during the titration period in the cannabis group (75.5%). The most common AEs were related to the nervous system (71.3%) and gastrointestinal system (41.3%). AEs were more frequent in cannabis patients compared to the placebo group; they included vertigo, attention disorder, equilibrium disorder, drowsiness, dry mouth, nausea, fatigue, weakness, diarrhea, urinary infection, confusion, and falls [23].

In another publication, after randomization to placebo or smoked cannabis (4% THC), 30 participants with MS were evaluated through 8 visits over a period of 2 weeks. Patients were asked to smoke once daily for 3 days, with an 11-day washout period between treatments. Each dose was an average of 4 puffs per cigarette. The sample was composed of 63% women with an average age of 50 years old; 70% of the participants were undergoing disease-modifying therapy, and 60% were taking antispasticity agents. Most of the participants (80%) had previous recreational experience with cannabis, and 33% had used cannabis within the previous year. Those who smoked cannabis had reduced patient scores for spasticity using the modified Ashworth scale by an average of 2.74 points and on VAS by 5.28 points more than placebo. It is worth mentioning that in this study, participants began with relatively low levels of pain. Smoking cannabis did increase patient perception of “highness” by 5.04 points more than placebo. Five patients withdrew from treatment due to adverse events: two patients felt uncomfortably “high”, two had dizziness, and one had fatigue [24].

In a double-blind placebo-controlled crossover study of 39 patients with neuropathic pain, inhalation of 10.3 mg of vaporized THC, divided into 2 sessions and separated by a 2 h interval, was associated with a 31 and 25% reduction in pain intensity at 3 and 5 h, respectively. Increasing the THC dose to 28.2 mg produced an equianalgesic response that remained stable when monitored at the same time intervals (3 and 5 h). The AEs were minimal, reversible, and well tolerated. Seven patients felt a sensation of light-headedness in the first minutes after inhalation, which regressed rapidly [25].

Doses of 0, 2.5, 6, and 9.4% THC were used in a population of patients with different types of neuropathic pain. Compared to placebo, a single inhalation with a low dose, 25 ± 1 mg cannabis containing 9.4% THC, administered 3 times a day for 5 days, was associated with an average Cmax of 45 ng/mL and a decrease of 11.4% in average daily pain intensity. Adverse events were THC concentration-dependent [26].

The effects of smoked cannabis were studied in patients affected by HIV-associated distal sensory predominant polyneuropathy (DSPN) and pain resistant to other analgesic drugs in a placebo-controlled double-blind crossover trial. Participants were treated with cannabis containing 1–8% THC or placebo 4 times a day for 5 consecutive days over a period of 2 weeks. After 2 weeks of washout, each group received the other treatment. Changes in pain intensity were evaluated together with possible modifications in mood and daily functioning. Cannabis produced the greatest pain relief in comparison to placebo. Both treatments ameliorated mood and daily functioning. Two participants were withdrawn from the study due to safety issues. In particular, one subject, naïve to cannabis, showed an acute psychosis with smoked cannabis. Another participant reported a severe but transitory cough caused by cannabis. Other minor AEs were a transitory increased cardiac rate, concentration deficit, drowsiness, fatigue, more prolonged sleep duration, sense of thirst, and reduced salivation [27].

In another placebo-controlled double-blind crossover study, 38 patients with central or peripheral neuropathic pain syndrome were asked to smoke cannabis with 7% THC or 3.5% THC or a placebo during three 6 h experimental sessions. The cumulative dose at each session was 9 puffs (2 puffs after 1 h, 3 puffs after 2 h, and 4 puffs after 3 h). The primary endpoint was based on VAS pain intensity before and after smoking marijuana. Cannabis produced an analgesic effect with cumulative dosing that began to reverse within 1–2 h after the last dose. The doses of 3.5 and 7% THC were equianalgesic at every time point, with no differences between the two over time. No significant differences in outcome were observed between the different pain conditions. “Feeling high” and “feeling stoned” were more prevalent in the active treatment groups and highest in the 7% THC group. “Feeling impaired” was higher in both treatment groups, but no significant difference was found between the higher and lower THC doses. Feelings of confusion, sedation, and hunger were also higher in the two active treatment groups. No mood changes were observed. A general cognitive decline was evident in both treatment groups, with greater cognitive impairment in the high-dose group [28].

In another study, 50 patients with painful HIV-associated sensory neuropathy were assigned to smoke either cannabis with 3.57% THC or placebo cigarettes 3 times daily for 5 days. Those who smoked cannabis had reduced daily pain by 34% compared with 17% in the placebo group, and 52% of patients in the cannabis group reported >30% pain reduction compared to 24% of patients in the placebo group. No serious AEs were reported in this study. Although there were few minor AEs, side effect ratings were higher in the cannabis group than the placebo group for anxiety, sedation, disorientation, confusion, and dizziness [29].

In the Cannabinoids in Multiple Sclerosis (CAMS) study, a clinical trial of 15 weeks that recruited 630 participants, 211 participants received an oral CE, 211 received THC, and 206 received placebo. The primary outcome was the effect of cannabis on the degree of spasticity as measured by the Ashworth scale. The active pharmacological treatment was a synthetic THC capsule (Marinol) and a cannabis extract containing 2.5 mg THC, 1.25 mg cannabidiol, and n = 121), 60% (n = 108), and 46% (n = 91) among those who received CE, synthetic THC, and placebo, respectively. This was regarded as a subjective rather than objective clinical effect. There were reports of SAEs in all groups, but they were more frequent in the placebo group. There were also minor AEs reported: frequent episodes of dizziness, light-headedness, or dry mouth in the active groups. There were some differences between groups in gastrointestinal side effects: constipation was more frequent in the cannabis extract group, and diarrhea was reported more in the active groups and not in the placebo group. Increased appetite was also a side effect in treatment groups, although with low frequency: four in the CE group, six in the THC group, and one in the placebo group [30].

A randomized double-blind placebo-controlled twofold crossover study evaluating the safety, tolerability, and efficacy of synthetic oral THC and Cannabis sativa plant extract was conducted with 16 patients with MS and severe spasticity (10 with secondary progressive MS and 6 with primary progressive MS). Each patient received the following 3 treatments for 4 weeks: synthetic THC (Dronabinol), Cannabis sativa extract, and placebo. During the first 2 weeks, study medications (THC and extract) were administered in twice daily doses of 2.5 mg THC or plant extract containing the same level of THC. If well tolerated, the dose was elevated to 5 mg twice a day for the next 2 weeks. There was a 4 week washout period between treatments. The primary outcome was a change in VAS score for pain. All patients completed the study. Six patients had used cannabis before, none on a regular basis. Both THC and plant-extract capsules were well tolerated. No SAEs were reported. AEs were more common during plant extract treatment. Five patients reported increased spasticity during plant extract treatment. One AE was rated as severe acute psychosis lasting for 5 h after the scheduled dose increase of plant extract. No clinically relevant changes were observed on physical examination or in hematology or chemistry measurements. Because of the limited sample size, no definite conclusions were reached, but the results of this study suggested there was no therapeutic benefit with either THC or plant extract treatment. The route of administration was cited as a possible explanation for the lack of efficacy. THC is absorbed reasonably well from the gut, but the process is slow, with large variations between and within individuals. A second possible explanation could be the prescribed dose. However, even at this dose, the number of AEs, especially during plant extract treatment, was rather high, suggesting that a higher dose might not be well tolerated [31].

4. Quality and Risk of Bias Assessment

Low-quality clinical trials can contain errors caused by processing the results, and consequently analyzing them can lead to distorted conclusions. Quality assessment is required to prevent clinical application of inaccurate results [32]. The Risk of Bias of included RCTs was assessed according to the Cochrane RoB 2.0 (Risk of Bias 2.0), which consists of five domains and an overall judgment. The five domains are the following: (1) bias arising from the randomization process; (2) bias due to deviations from the intended interventions; (3) bias due to missing outcome data; (4) bias in measurement of the outcome; and 5) bias in selection of the reported result. Based on the answers (yes, probably yes, probably no, no, not applicable, no information) to a series of signaling questions, the judgment options within each domain consist of “low risk of bias”, “some concerns”, or “high risk of bias” [33].

According to the guidance document RoB2 recommendations, 10 of 15 studies collected [17,20,22,23,24,25,26,28,29,30] in the present article can be considered at low risk of bias. For both the two studies of Ellis et al., 2009 [27] and Killestein et al., 2002 [31], assessment of risk of bias puts in evidence a bias as a result of deviation from intended interventions. For the remaining three studies [18,19,21] assessment was not applicable ( Table 3 ).