Analgesic Actions of CBs in Humans

16 May

Reports from animal studies provide strong evidence to support the analgesic effects of CBs; however, studies in human volunteers and patients are at a much earlier stage and the evidence is, at present, weak. Nevertheless, patient surveys report  the use of cannabis  for pain  relief: in a recent  survey of 2,969 UK patients,  medicinal use of cannabis  is reported  by those with chronic pain (25%) multiple sclerosis (22%), arthritis (21%) and neuropathy  (19%) (Ware et al. 2005). Of a sample of 209 Canadian chronic non-cancer  pain sufferers,

15% reported having used cannabis at least once for the control of their pain, with approximately 38% using cannabis at least daily (Ware et al. 2003). There is also evidence that  a significant proportion of people living with human immunodeficiency virus (HIV) in London use cannabis for symptom control (Woolridge et al. 2005).

Evidence from Volunteer Studies

There  is a relatively small literature  on  the  effects of CBs in human  vol- unteer  models of pain. Application of HU210 to human  skin has been re- ported  to have inhibitory  effects on  histamine-evoked  itch (Dvorak  et al.

2003) and  capsaicin-evoked  pain  responses  (Rukwied et al. 2003). In  the latter study, the rate of increase in pain intensity following capsaicin appli-

cation was lower in the HU210-treated compared  to the placebo (ethanol)- treated  group, and a similar temporary  slowing in the development  phase

of capsaicin-associated  mechanical allodynia was reported.  However, there was no overall difference in pain  intensity.  Anti-nociceptive  properties  of smoked marijuana  have also been reported  in a noxious thermal  stimulus withdrawal  test  (Greenwald  and  Stitzer 2000). In  contrast,  a study  on  12

volunteers  reported  that  a single does of oral THC (20 mg) did not  have significant anti-nociceptive  effects on responses  to thermal,  mechanical  or

electrical stimuli.  Interestingly,  30 mg of morphine  was effective in most of the tests, and some analgesic effects were reported  when THC was ad- ministered with 30 mg of morphine  before electrical stimulation  (Naef et al. 2003).

Evidence from Randomised Controlled Clinical Trials

The data  from clinical trials to date indicate  that  the efficacy of currently available CBs in humans is modest and that their effectiveness is hampered by an unfavourable therapeutic index.

A qualitative systematic review of trials published  up to 1999 identified nine clinical trials of CBs of sufficient quality for inclusion  in the analysis (Campbell et al. 2001). Five of these trials used cancer pain as a model, two used chronic non-malignant pain and two acute pain. Most of the trials examined

the effects of either Δ9THC or levonantradol. The analgesic effect of these CBs was estimated to be approximately equi-analgesic to codeine 50–120 mg, but adverse effects were common, being reported in all studies. One study showed

the adverse effects to be dose-related and it is possible that these obfuscated a greater analgesic effect at the higher dose of Δ9THC which was examined (Noyes et al. 1975).

Since 1999, several clinical trials have been published in which the anal-

gesic effects of CBs in chronic, especially neuropathic,  pain conditions  were investigated. One trial examined the efficacy of CBs in alleviating neuropathic symptoms in multiple sclerosis (Wade et al. 2003). In this study, a self-titration

regimen was used in which either plant-derived Δ9THC, cannabidiol, a 1:1 mix- ture of Δ9THC and cannabidiol, or placebo were administered  by sublingual spray. Data on a range of symptoms were collected and modest analgesic effects

were evident. Whilst the fixed ratio preparation (mean dose 22 mg/day) was not associated with a significant reduction  in baseline pain intensity scores, Δ9THC (23.5 mg/day)  and cannabidiol  (22 mg/day)  were, when compared to the effect of placebo. Adverse effects were common; 30%–67% of subjects

reporting  more than one adverse event, and 17% of patients withdrew from the trial because of adverse effects. A cross-over trial of 24 multiple sclero- sis patients  with central pain investigated the effects of a 3-week course of

daily treatment  with oral dronabinol (maximum 10 mg dose) (Svendsen et al.

2004). The authors report a modest but significant analgesic effect of the active treatment on median spontaneous pain intensity scores, calculating a number needed to treat (NNT) value for 50% pain relief at 3.5. A study of 48 patients with central neuropathic  pain resulting from brachial plexus avulsion injury reported that short-term treatment  with oral cannabis extract (as an adjunct to existing medication) revealed no improvement in the primary pain efficacy measure (Berman et al. 2004). Furthermore,  a complicated trial of 21 patients with chronic neuropathic  pain, in which patients received two daily doses of

ajulemic acid (the synthetically modified metabolite of THC) for a week, did reveal evidence of analgesic efficacy for this compound (Karst et al. 2003). No significant effects of the drug on mechanical hypersensitivity were reported in this trial; however, there was evidence of an analgesic effect. Pain relief from conventional CBs was also measured as a secondary outcome in a very large study in multiple sclerosis patients (Zajicek et al. 2003): although there was no effect of CBs on the primary efficacy measures, a modest analgesic effect was reported.


In addition to efficacy, adverse effects are important in determining the clin- ical effectiveness of any novel therapy, and an acceptable therapeutic  index for short-term  adverse events will have to be proved for CBs. Furthermore, concerns relating to the long-term risk of developing mental illness in regular cannabis users have obvious relevance for the patients  electing to undergo long-term, regular medication  with CBs in conditions  such as chronic pain. For example, a 27-year cohort  study of 50,000 Swedish military conscripts found a dose-dependant increased risk of schizophrenia  (once confounding factors such as cannabis  use in prodromal  schizophrenia  and concomitant drug abuse had been excluded) in regular cannabis users (Zammit et al. 2002). Similar findings for depression and anxiety (Patton et al. 2002) and psychosis (Arseneault  et al. 2002; D’Souza et al. 2004; Henquet  et al. 2005) have also been reported in smaller cohort studies. There is also evidence that the risk of cannabis-induced psychosis is substantially greater in those individuals who have a predisposition to developing psychosis (Henquet et al. 2005) or genetic functional polymorphisms  (Caspi et al. 2005). There are also data indicating cumulative, dose-dependent deficits in cognitive function in regular cannabis users (Solowij et al. 2002).

Concluding Remarks

There are compelling laboratory data supporting the analgesic effects of CBs; however, before CB-based drugs can be used therapeutically in humans, they must be shown to be both effective and safe in long-term regular use. Well- designed clinical trials are therefore required, but are perhaps premature until suitable CBs with a satisfactory therapeutic  index for analgesia and proven bioavailability when administered  by a practical route of administration are available for human  study. Current  strategies to circumvent  side-effects but retain analgesic efficacy include the development of non-psychoactive or pe- ripherally active CBs, such as cannabidiol,  ajulemic acid and CB2 receptor

selective agonists (Fride et al. 2004; Salim et al. 2005; Ibrahim  et al. 2005). Whilst new drugs are being trialled, the prospective clinical uses for CBs could lie with chronic pain patients in whom fear contributes to abnormal pain be- haviour (Marsicano et al. 2002) or in situations  where the adverse effects of CBs might confer additional  benefit over existing therapies, for example by exploiting their anti-inflammatory or anti-emetic properties.

Acknowledgements   The authors receive support from the Wellcome Trust.

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