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LETTERS TO THE EDITOR

Comments on "Cannabimimetic Properties of Ajulemic Acid"

Hannover Medical School, Hannover, Germany

Received April 17, 2007; accepted April 17, 2007.

Vann et al. (2007) recently published data showing psychoactive and therapeutic effects of AJA at "nearly equal" doses in preclinical models, suggesting similar limitations in the clinical situation. Although it was recognized that the clinical study (Karst et al., 2003; Salim et al., 2005) did not show any specific cannabimimetic properties of AJA at daily doses up to 80 mg, a considerable analgesic effect at this dose was challenged (Vann et al., 2007; Wiley, 2007). With respect to the clinical study with AJA, the following points should be considered.

1. AJA produced in the AJA-placebo group a score difference of 13 (visual analog scale, 0–100) and in the placebo-AJA group a difference of 13 (visual analog scale, 0–100). This corresponds to a pain reduction of 29 and 18%, respectively. Compared with the respective placebo sequence score of 20, these endpoints are clinically and statistically different with p = 0.02 (Karst et al., 2003). This is also reflected in responder rates (30% or more pain reduction): 67% (6/9) response rate on active versus 20% (2/10) response rate on placebo in the 1st intervention week and 30% (3/10) response rate on active versus 11% (1/9) on placebo in the 2nd intervention week (Salim et al., 2005).
   
2. The challenging question is whether an average decline of 13 points on a scale of 0 to 100 is meaningful for people suffering chronic pain. A 13-point difference can be compared with that obtained by other commonly used treatments for neuropathic pain. For example, to achieve this effect, 67% of the participants in a placebo-controlled study using gabapentin for painful diabetic neuropathy required the maximum daily dose of 3600 mg (Backonja et al., 1998). A recent Cochrane review on opioids for neuropathic pain showed a 13-point difference in pain intensity at the end of the study compared with placebo (Eisenberg et al., 2006). Thus, opioids were assessed as favorable compounds for intermediate-term treatment of spontaneous neuropathic pain.
   
3. The observation that pain reduction at the second time of assessment at 4:00 PM (Karst et al., 2003; Salim et al., 2005) did not produce statistical significance is not likely a matter of efficacy but that of the pharmacokinetic properties of AJA. In healthy human volunteers, peak plasma concentrations were reached in most participants at 1 or 2 h after absorption from the gastrointestinal tract (Karst et al., 2003). Therefore, a shorter dosing interval, such as 6 to 8 h, should be considered.
   
4. A strong tendency (p = 0.052) toward decreasing pain sensitivity after treatment with AJA was observed (Salim et al., 2005). Although statistical significance was not obtained, this observation may be meaningful because most clinical studies fail to detect treatment effects on pain thresholds in response to mechanical or thermal stimuli. Animal experiments have revealed that AJA has antiallodynic properties (Burstein et al., 2004; Mitchell et al., 2005).
   
5. The magnitude of the effect on the pain measurements is all the more relevant because the study population consisted of refractory, long-standing, and severe traumatic neuropathic pain patients with hyperalgesia and allodynia (Karst et al., 2003).
   
6. Only one AJA-related withdrawal (5%) was observed, and that occurred with comedication of 800 mg of morphine equivalents per day (Karst et al., 2003). Compared with opioids, this is a low rate. The Cochrane review of opioids for neuropathic pain found a withdrawal rate of 11% (Eisenberg et al., 2006). Furthermore, in the AJA clinical study of 19 patients, only 12 reported mild adverse events with no THC-like alteration of consciousness (Salim et al., 2005). Elevation of AJA dosage from 40 to 80 mg daily did not show a significant increase of reported adverse events.
   
7. Interestingly, some animal studies of neuropathic pain showed clear species differences in the activity of different compounds. For example, oxcarbazepine and carbamazepine did not affect mechanical hyperalgesia or tactile allodynia induced by partial sciatic nerve ligation in the rat. However, using the same model in the guinea pig, both drugs produced up to 90% reversal of mechanical hyperalgesia (Fox et al., 2003). These findings reveal that data generated from different species may not be easily translated to other species.
   

In summary, the clinical trial on AJA found that AJA in the dose range from daily 40 to 80 mg showed a favorable therapeutic index for neuropathic pain. Proof of concept trials (phase 2a) are designed to provide initial efficacy but not a precise estimate of the efficacy, which will be obtained in larger subsequent trials over a longer period of time.

	Footnotes

 
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

doi:10.1124/jpet.107.124214.

ABBREVIATIONS: AJA, ajulemic acid; THC, tetrahydrocannabinol.

	References

Top References

 

Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V, Hes M, LaMoreaux L, and Garofalo E (1998) Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 280: 1831-1836.[Abstract/Free Full Text]

Burstein SH (2007) In humans, ajulemic acid has a more favorable side-effect profile than THC for the treatment of chronic neuropathic pain. Cannabinoids 2: 1-2.

Burstein SH, Karst M, Schneider U, and Zurier B (2004) Ajulemic acid: a novel cannabinoid produces analgesia without a "high". Life Sci 75: 1513-1522.[CrossRef][Medline]

Eisenberg E, McNicol E, and Carr DB (2006) Opioids for neuropathic pain (review). Cochrane Database of Systematic Rev 3: CD006146.

Fox A, Gentry C, Patel S, Kesingland A, and Bevan S (2003) Comparative activity of the anti-convulsants oxcarbazepine, carbamazepine, lamotrigine and gabapentin in a model of neuropathic pain in the rat and guinea-pig. Pain 105: 355-362.[CrossRef][Medline]

Karst M, Salim K, Burstein S, Conrad I, Hoy L, and Schneider U (2003) Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain. JAMA 290: 1757-1762.[Abstract/Free Full Text]

Mitchell VA, Aslan S, Safaei R, and Vaughan CW (2005) Effect of the cannabinoid ajulemic acid on rat models of neuropathic and inflammatory pain. Neurosci Lett 382: 231-235.[CrossRef][Medline]

Salim K, Schneider U, Burstein S, Hoy L, and Karst M (2005) Pain measurements and side effect profile of the novel cannabinoid ajulemic acid. Neuropharmacology 48: 1164-1171.[CrossRef][Medline]

Vann RE, Cook CD, Martin BR, and Wiley JL (2007) Cannabimimetic properties of ajulemic acid. J Pharmacol Exp Ther 320: 678-686.[Abstract/Free Full Text]

Wiley JL (2007) Letter: preclinical assessment of abuse liability of ajulemic acid. Cannabinoids 2: 3-4.

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