A Phase II, multicenter, randomized, double-blind, placebo-controlled crossover study of CJC-1008—a long-acting, parenteral opioid analgesic—in the treatment of postherpetic neuralgia

Mark S. Wallace, MD, Dwight Moulin, MD, A. J. M. Clark, FRCPC, Ronald Wasserman, MD, Ann Neale, Patricia Morley-Forster, MD, Jean-Paul Castaigne, MD, Sam Teichman, MD


Introduction: CJC-1008 is a chemical modification of the opioid peptide dynorphin A (1-13) (Dyn A) that promotes dynorphin’s covalent attachment to human serum albumin in vivo after administration, thus prolonging its duration of action. The primary objective of this study was to evaluate the preliminary efficacy and safety of CJC-1008 as compared with placebo in patients with postherpetic neuralgia (PHN).
Methods: Patients with PHN were assigned 1:1 to receive active study medication or placebo. After dosing, measurements were made every 15 minutes for the first hour; at two, three, four, six, and eight hours postdose; and during return visits to the study site after two, seven, and 28 days (as necessary), as well as during precrossover and exit visits. These measurements examined: 1) overall pain intensity, 2) pain intensity for each individual PHN type, 3) categorical overall pain intensity, 4) categorical pain relief, and 5) adverse events (AEs). When PHN pain intensity returned to baseline and/or at patients’ first request for rescue analgesia other than acetaminophen (typically around 28 days after dosing but sometimes as soon as two days postdose), patients were to cross over to the alternative treatment and be monitored on the same schedule.
Results: A substantial placebo response was observed, but the analgesic effect observed in the active group was greater than that in the placebo group for the first eight hours. By 24 hours, the difference was not significant. A total of 29 out of 30 patients (96 percent) experienced at least one treatment-emergent AE during active drug treatment, while 14 of 27 patients (52 percent) reported such AEs during placebo treatment. Of the AEs occurring within the first eight hours after dosing, 97 percent were reported during treatment with active drug and 3 percent were reported during treatment with placebo. The majority of these AEs were mild in intensity.
Discussion: This study provides evidence of a greater analgesic effect when using CJC-1008 compared to placebo in patients with PHN. However, the effect only lasted through eight hours postdose and diminished by 24 hours. This study provides evidence of a peripheral action of dynorphin, since CJC-1008 does not cross the blood-brain barrier.


CJC-1008, dynorphin, postherpetic neuralgia, placebo response

Full Text:



Fields HL, Rowbotham M, Baron R: Postherpetic neuralgia: Irritable nociceptors and deafferentation. Neurobiol Dis. 1998; 5(4): 209-227.

Greenwald MK, Stitzer ML, Haberny KA: Human pharmacology of the opioid neuropeptide dynorphin A (1-13). J Pharmacol Exp Ther. 1997; 281: 1154-1163.

Chou JZ, Chait BT, Wang R, et al.: Differential biotransformation of dynorphin A (1-17) and dynorphin A (1-13) peptides in human blood, ex vivo. Peptides. 1996; 17: 983-990.

Muller S, Hochhaus G: Metabolism of dynorphin A 1-13 in human blood and plasma. Pharm Res. 1995; 12: 1165-1170.

Irwin S, Houde RW, Bennett DR, et al.: The effects of morphine, methadone and meperidine on some reflex responses of spinal animals to nociceptive stimulation. J Pharmacol Exp Ther. 1951; 101: 132-143.

Allen DT, Kiernan JA: Permeation of proteins from the blood into peripheral nerves and ganglia. Neuroscience. 1994; 59: 755-764.

Lynch JJ III, Jarvis MF, Kowaluk EA: An adenosine kinase inhibitor attenuates tactile allodynia in a rat model of diabetic neuropathic pain. Eur J Pharmacol. 1999; 364(2-3): 141-146.

Portenoy RK, Duma C, Foley K: Acute herpetic and postherpetic neuralgia: Clinical review and current management. Ann Neurol. 1986; 20: 651-664.

Portenoy RK: Neuropathic pain. In Portenoy RK, Kanner RM (eds.): Pain Management: Theory and Practice. Philadelphia: FA Davis Co., 1996.

Galer BS, Rowbotham MC, Perander J, et al.: Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch: Results of an enriched enrollment study. Pain. 1999; 80: 533-538.

Dworkin RH, Corbin AE, Young JP Jr, et al.: Pregabalin for the treatment of postherpetic neuralgia: A randomized, placebo-controlled trial. Neurology. 2003; 60: 1274-1288.

Rowbotham M, Harden N, Stacey B, et al.: Gabapentin for the treatment of postherpetic neuralgia: A randomized controlled trial. JAMA. 1998; 280: 1837-1863.

Max MB: Treatment of post-herpetic neuralgia: Antidepressants. Ann Neurol. 1994; 35: S50-S53.

Pappagallo M, Campbell JN: Chronic opioid therapy as alternative treatment for post-herpetic neuralgia. Ann Neurol. 1994; 35: S54-S56.

Herz A: Multiple opiate receptors and their functional significance. J Neural Transm Suppl. 1983; 18: 227-233.

Przewlocki R, Stala L, Greczek M, et al.: Analgesic effects of mu-, delta- and kappa-opiate agonists and, in particular, dynorphin at the spinal level. Life Sci. 1983; 33(suppl. 1): 649-652.

Vanderah TW, Ossipov MH, Lai J, et al.: Mechanisms of opioid-induced pain and antinociceptive tolerance: Descending facilitation and spinal dynorphin. Pain. 2001; 92(1-2): 5-9.

Ossipov MH, Kovelowski CJ, Wheeler-Aceto H, et al.: Opioid antagonists and antisera to endogenous opioids increase the nociceptive response to formalin: Demonstration of an opioid kappa and delta inhibitory tone. J Pharmacol Exp Ther. 1996; 277(2): 784-788.

Knox RJ, Dickenson AH: Effects of selective and non-selective kappa-opioid receptor agonists on cutaneous C-fibreevoked responses of rat dorsal horn neurones. Brain Res. 1987; 415: 21-29.

Willcockson WS, Kim J, Shin HK, et al.: Actions of opioids on primate spinothalamic tract neurons. J Neuroscience. 1986; 6: 2509-2520.

Stein C: Peripheral mechanisms of opioid analgesia. Anesth Analg. 1993; 76(1): 182-191.

Hassan AH, Przewlocki R, Herz A, et al.: Dynorphin, a preferential ligand for kappa-opioid receptors, is present in nerve fibers and immune cells within inflamed tissue of the rat. Neurosci Lett. 1992; 140(1): 85-88.

Stein C, Hassan AH, Przewlocki R, et al.: Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation. Proc Natl Acad Sci U S A. 1990; 87(15): 5935-5939.

Cabot PJ, Carter L, Schafer M, et al.: Methionine-enkephalin- and Dynorphin A-release from immune cells and control of inflammatory pain. Pain. 2001; 93(3): 207-212.

Beyer A, Schafer M, Stein C: Antinociceptive effects of dynorphin peptides in a model of inflammatory pain. Pain. 1997; 70(2-3): 141-147.

Shibata M, Ohkubo T, Takahashi H, et al.: [Peripheral analgesic actions of opioid peptides and morphine analogues]. Nippon Yakurigaku Zasshi. 1986; 88(2): 101-107.

Kreek MJ, Schluger J, Borg L, et al.: Dynorphin A1-13 causes elevation of serum levels of prolactin through an opioid receptor mechanism in humans: Gender differences and implications for modulation of dopaminergic tone in the treatment of addiction. J Pharmacol Exp Ther. 1999; 288: 260-269.

Wen HL, Ho WK: Suppression of withdrawal symptoms by dynorphin in heroin addicts. Eur J Pharmacol. 1982; 82: 183-186.

Specker S, Wananukul W, Hatsukami D, et al.: Effects of dynorphin A(1-13) on opiate withdrawal in humans. Psychopharmacology. 1998; 137: 326-332.

Gambus PL, Schnider TW, Minto CF, et al.: Pharmacokinetics of intravenous dynorphin A(1-13) in opioid naive and opioid-treatment human volunteers. Clin Pharmacol Ther. 1998; 64: 27-38.

Barke KE, Hough LB: Simultaneous measurement of opiateinduced histamine release in the periaqueductal gray and opiate antinociception: An in vivo microdialysis study. J Pharmacol Exp Ther. 1993; 266: 934-942.

Barke KE, Hough LB: Opiates, mast cells and histamine release. Life Sci. 1993; 53: 1391-1399.

Gustorff B, Nahlik G, Hoerauf KH, et al.: The absence of acute tolerance during remifentanil infusion in volunteers. Anesth Analg. 2002; 94(5): 1223-1228, table of contents.

DOI: https://doi.org/10.5055/jom.2006.0026


  • There are currently no refbacks.