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B Frank, M G Serpell, J Hughes, J N S Matthews, and D Kapur
Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study
BMJ 2008; 336: 199-201 [Abstract] [Full text]

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Response to the paper of Frank et al � Cannabinoids and Opioids Cannot Be Considered Mutually Exclusive and Not All Neuropathic Pain States Can Be Considered Equal: Cory C. Toth, Michael Namaka (7 May 2008)

Response to the paper of Frank et al � Cannabinoids and Opioids Cannot Be Considered Mutually Exclusive and Not All Neuropathic Pain States Can Be Considered Equal 7 May 2008

Cory C. Toth,
Neurologist
University of Calgary, Calgary, Alberta, Canada, T2N4N1,
Michael Namaka
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Re: Response to the paper of Frank et al � Cannabinoids and Opioids Cannot Be Considered Mutually Exclusive and Not All Neuropathic Pain States Can Be Considered Equal

We read, with interest, the publication by Frank and colleagues reporting the results of a randomized, double blinded, crossover 14 week controlled trial comparing the effectiveness of the synthetic cannabinoid nabilone with dihydrocodeine (DHC) for neuropathic pain (NeP) conditions.(1) This study examined a total of 96 patients with great diversity in patient demographics and origins of their NeP conditions. There are a number of difficulties with performance and analysis of their study which may limit its generalization to the general population in countries where cannabinoid drugs may be prescribed.
Despite the obvious diversities amongst the entire patient population recruited for this study, a comparative statistical analysis between the two initial study groups was not conducted. Readers were not assured that statistical significant differences were absent between the treatment groups. Furthermore, there was an abundance of post-traumatic neuropathic pain (PTNeP), which can often be associated with features of the more refractory complex regional pain syndrome (CRPS). The authors did not provide information regarding their definition of PTNeP and CRPS and their differentiation. In addition, they also did not specifically describe the latency of time between the surgical or injury-related insult and subsequent entry into this clinical study. Both PTNeP and CRPS are difficult to treat,(2-3) so inclusion of a large number of these patients would significantly modify outcomes in this study. The generic reporting of these patients receiving DHC or nabilone represents a very significant portion (22/34 and 20/39 respectively) of recruited patients, and discrepancies in the severity and refractoriness in their PTNeP or CRPS could account for a lack of beneficial effect for the 2 agents studied. It is likely that appropriate subanalyses would demonstrate an obvious lack of power to detect meaningful differences between individual causes of NeP, thereby questioning the results obtained.
Allodynia, unusual to be part of diagnostic criteria in most similar studies of NeP, was listed as such in the study of Frank et al,(1) yet nearly 40% of patients studied did not have signs of allodynia according to Table 2. There were no descriptions of any mechanism by which patients were determined to have allodynia. Sympathetic dysfunction was also listed as a diagnostic criterion, but there was no indication of its determination either; i.e. was this based upon autonomic nervous system testing in a certified laboratory, or was it simply based upon a symptom described by a patient, such as swelling over the affected area? Regardless, the presence of allodynia and sympathetic dysfunction are unlikely to be commonly present in patients with NeP. Furthermore, the threshold of 40 mm on the VAS pain scale may not have been followed for study inclusion, as the stated baseline VAS score range was 29.4-95.2.
The chosen duration of study for each individual agent was only six weeks, far too short to detect longer positive or negative effects of therapies used for chronic conditions such as NeP. Such a short period of time easily exposes itself to �ebbs and flows� in NeP which are commonly seen in many patients. In relation to this, the achieved benefit of either nabilone or DHC was small, perhaps related to the short duration of study intervention; benefits of ~15% were seen, which are much smaller, or at least similar, to the benefit of placebo in most published studies. This small benefit may be attributed to underdosing of a fixed dose nabilone (only 2 mg daily when suggested maximum dosing ranges between 4-6 mg daily), or associated stigma with the use of cannabinoids due to continuing cultural-political context regarding cannabis. Non-flexible dosing of nabilone may have also contributed to noted side effects as well as undertreatment of the painful condition. As well, the use of rescue mediations and the continuation of previously used analgesics may have contributed to adverse effects and the dampening of pain benefits seen with either nabilone or DHC, although this was not mentioned. Examination of Table 2 does not show assessment of comorbidities or other medication use present in patients studied. Furthermore, the large drop out rates (23/96 after randomization and only 64/96 supplying data for per protocol analysis) in such a short duration further complicate assessment of this data and its extrapolation to a large clinical population. Finally, the potential long term effects of DHC, particularly hepatic, were not considered by the authors and would not be evident in this short study but could certainly complicate long term use of DHC.
The authors imply that nabilone does not have any effect upon opioid receptors, and therefore can be studied as a contrast to the weak opioid DHC. First, this is incorrect, as there are both indirect effects of cannabinoids upon opioid receptors(4-5) and direct effects via opioid agonism.(6-8) Specifically, combining cannabinoids with opioids has been shown in various laboratory animals to enhance the analgesic effect of the opiod,(9) prevent the development of tolerance and physical dependence,(10) and extend the duration of action of both morphine and codeine.(11) Overall, this could extrapolate to question the validity of a cross-over study using a mild opioid that does not have a proper washout period. Consequently, the specified 2 week washout period in the study of Frank et al(1) may not be sufficient, and carry-over effects need to be considered. Furthermore, codeine, another mild opioid, was permitted as rescue medication, potentially interfering further with the opioid receptor status impacted by nabilone or DHC use. Overall, we do not agree with their choice of comparative agent selected for this study.
Although this study implied that nabilone led to more adverse effects, there is no statistical confirmation of this provided in the manuscript. In fact, evaluation of Figure 2 suggests that more withdrawals occurred with DHC compared with that of nabilone. From the 32 patients that withdrew from the study, a total of 16 patients withdrew specifically due to drug related adverse events; while 12 of 16 patients withdrew due to adverse events associated with the use of DHC, just 4 patients withdrew in the nabilone treated group.
Finally, there is no determination of NeP presence made throughout the study. We are left to assume that a pain specialist determined the nature of pain in each individual case, but we are uncertain. Reasonably specific and sensitive questionnaires for NeP such as the DN4 (sensitivity 82.9%;sensitivity 89.9%)(12) and the LANSS (sensitivity 80%;sensitivity 80%)(13) exist, and could easily have been used to verify the nature of pain. This inability to separate pain conditions leaves readers concerned that other classifications of pain may have inadvertently entered into the study.
In conclusion, it is difficult to extrapolate the study of Frank et al(1) to a general chronic pain population. It does not prove that nabilone is less beneficial for NeP management than DHC, nor does it suggest that side effects are more plentiful with one management or the other. Further long-term studies with the cannabinoids will be required using more appropriate comparative agents, flexible dosing schedules, improved and more strictly adhered-to diagnostic criteria and inclusion criteria, and a more appropriate duration of study. Only studies designed and performed in this manner will determine if the benefits of cannabinoids upon NeP identified in numerous animal studies can be reproduced in human studies.
Sincerely,
Cory Toth, BSc, MD, FRCPC (Neurology) Assistant Professor of Clinical Neurosciences University of Calgary
Michael Namaka BSc, Ph D, MS-CA Assistant Professor/Neuroscientist Faculty of Pharmacy University of Manitoba
References
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Competing interests: None declared