Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study

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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analgesic effects and patient tolerability of nabilone and dihydrocodeine
for chronic neuropathic pain: randomised, crossover, double blind study.
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Competing interests:
None declared