In this randomized clinical trial, smoked cannabis at maximum tolerable dose (1–8% THC), significantly reduced neuropathic pain intensity in HIV-associated DSPN compared to placebo, when added to stable concomitant analgesics. Using verbal descriptors of pain magnitude from DDS, cannabis was associated with an average reduction of pain intensity from ‘strong’ to ‘mild to moderate’. Also, cannabis was associated with a sizeable (46%) and significantly greater (vs
18% for placebo) proportion of patients who achieved what is generally considered clinically meaningful pain relief (eg ≥30% reduction in pain; Farrar et al, 2001
). Mood disturbance, physical disability, and quality of life all improved significantly for subjects during study treatments, regardless of treatment order.
A recently published, influential review concluded that the potential medicinal benefits of cannabis, including analgesia for neuropathic pain, warranted further high quality research (Watson et al, 2000
). We employed methodological criteria generally regarded as essential for establishing the validity of treatment outcome research in chronic pain syndromes, including rigorous specification of neurologic diagnosis, randomization and placebo control, assessment of study blinding, tracking of cointerventions, and an individualized dosing strategy designed to optimize outcomes (Deyo, 1983
). The study sample is arguably representative of clinic populations of painful HIV DSPN, given the duration and stage of HIV disease, use of concurrent analgesics, as well as history of exposure to ARV agents known to be associated with painful DSPN.
This study’s findings are consistent with and extend other recent research supporting the short-term efficacy of cannabis for neuropathic pain. Thus one recent, inpatient randomized clinical trial of painful DSPN noted that inhaled cannabis, in doses comparable to those in the present report, significantly reduced pain intensity (34%) compared to placebo (17%; Abrams et al, 2007
). Our findings extend the efficacy of cannabis to individuals with intractable pain, as our cohort had substantially greater number of subjects taking concomitant analgesics (100%) than did Abrams et al
(22%). Most of our subjects took concomitant opioid therapy and almost all took at least one other concurrent pain-modifying medication. This afforded us the opportunity to evaluate potential pharmacodynamic interactions, such as synergy with opioids, as suggested by previous investigators. We observed no interaction (positive or negative synergism) between opioids and cannabis. Two other placebo-controlled studies of neuropathic pain associated with multiple sclerosis indicated that both sublingual Δ-9-THC alone or with cannabidiol (Rog et al, 2005
), and oral synthetic Δ-9-THC (Svendsen et al, 2004
) significantly outperformed placebo. As regards the pain benefits of cannabis compared to other available therapies for painful DSPN, as assessed by NNT: our results (NNT = 3.5) are equivalent to those achieved by Abrams et al (2007)
(NNT = 3.6), are in the range of the leading anticonvulsants (lamotrigine, NNT = 5.4; gabapentin, NNT = 3.8) (Simpson et al, 2003
; Backonja, 2002
) and are superior to null results obtained for amitriptyline (Kieburtz et al, 1998
; Shlay et al, 1998
) and mexiletine (Kieburtz et al, 1998
Blinding in this study was performed using conventional measures, which included randomization of subjects to treatment assignments known only to the study pharmacist. We expected that because the prominent psychoactive effects of cannabis would distinguish it from placebo—as is true for other potent analgesic agents such as opioids—
some subjects would correctly ‘guess’ their treatment assignment. To evaluate preservation of the blind, we asked each subject to report his or her impression of what treatment they received at several time points during the study as previously described. Blinding was considered to be preserved when the accuracy of treatment guesses was no different from random guessing (50%). Correct guessing was related to two factors: first, whether the subject received placebo or cannabis first; and second, when during the study they were asked to make their guess. Thus among subjects randomized to receive placebo first, guessing was no better than chance through the end of the first treatment week, whereas among subjects randomized to receive cannabis first, the majority correctly guessed their treatment assignment at all time points. Furthermore, by the second treatment week, when all subjects had been given the opportunity to compare the cannabis placebo and treatments, even those randomized to receive placebo first correctly guessed their treatment assignment. These findings raise the possibility that some of the DDS pain reduction was placebo driven. To assess whether correct treatment guessing influenced treatment responses, we performed secondary analyses showing that in the placebo group during the first treatment week, when guessing was no better than chance, cannabis still provided pain relief superior to that of placebo. This finding suggests that although placebo effects were present, treatment effects were independent.
Several other potential limitations were addressed. Attrition, approximately 18%, was somewhat higher than projected, but was within the range of other trials of HIV-associated and other painful neuropathic syndromes (Kieburtz et al, 1998
; Max et al, 1992
; Shlay et al, 1998
; Simpson et al, 2003
). However, an ITT sensitivity analysis demonstrated that the superiority of cannabis was robust to reasonable assumptions about the treatment responses of the dropouts. We included subjects with DSPN related either to HIV itself or to nucleoside ARV drug exposure; a more homogeneous sample may have had a different outcome. Finally, durability of analgesia, which is of paramount concern in chronic pain syndromes, could not be assessed in this short-term study. Because DDS is a relatively complex instrument for capturing pain reports, its validity and reliability might be limited by confusion and sedation during cannabis treatment. We therefore considered a simpler pain assessment tool, VAS, which is less susceptible to confounding by neurocognitive side effects. Similar to DDS, VAS also showed superior analgesia with cannabis.
The therapeutic application of cannabis depends on palatability and safety concerns as well as efficacy. Smoking is not an optimal delivery system. Long-term use of smoked cannabis is associated with symptoms suggestive of obstructive lung disease, and although short-term use is not (Tetrault et al, 2007
), many individuals cannot tolerate smoking. Alternative administration routes for cannabinoids, including vaporization and mucosal sprays, are currently approved for clinical use in Great Britain and Canada and are under evaluation in the United States. Cannabis has potent psychotropic effects including ‘paradoxical’ effects (eg depersonalization, hallucination, suspiciousness) in an important minority of individuals (Hall and Solowij, 1998
). A recent meta-analysis suggested an increased risk of psychotic illness in individuals who had ever used cannabis (Moore et al, 2007
), although it was acknowledged that vulnerability to psychotic disorder and use of cannabis may be confounded.
Our findings suggest that cannabinoid therapy may be an effective option for pain relief in patients with medically intractable pain due to HIV-associated DSPN. As with all analgesics, dose limiting side effects should be carefully monitored, particularly during the initial trials of therapy.