Physicians from Purdue Pharma LP (Stamford, CT, USA) have announced results from a 12-week study demonstrating the analgesic efficacy and safety of buprenorphine (BuTrans®) for the relief of moderate-to-severe chronic lower back pain in opioid-naive patients. BuTrans is a new treatment for chronic back pain approved by the US FDA in June 2010. It provides systemic delivery of buprenorphine continuously over a 7-day period via a transdermal delivery system.
The trial‘s primary efficacy outcome, the “average pain over the last 24 h” at week 12, resulted in a statistically significant treatment difference.
The safety and efficacy of BuTrans was tested in a randomized, double-blind study, where 1024 patients were treated with BuTrans during the open-label run-in period. Patients were randomized to BuTrans 10 and BuTrans 20 or matching placebos.
“In the open-label run-in period, if BuTrans 10 was tolerated but adequate analgesia was not reached, the dose was increased to BuTrans 20 for an additional 10 to 12 days” explained Deborah Steiner, medical director at Purdue Pharma. “Patients who achieved adequate analgesia and tolerated BuTrans were then randomized to remain on the titrated dose of BuTrans (10 or 20) or a matching placebo. To demonstrate adequate analgesia in the open-label run-in period, patients had to have pain scores of less than or equal to four on an 11-point scale for three consecutive days and at least a 2-point reduction from their screening pain scores.”
The trial‘s primary efficacy outcome, the “average pain over the last 24 h” at week 12, resulted in a statistically significant treatment difference of -0.58 in favor of BuTrans over placebo (p = 0.0104). The proportions of patients with at least 30% and at least 50% pain score improvements were larger for BuTrans-treated patients.
“We were able to demonstrate that BuTrans was superior to placebo in treating opioid-naive patients with moderate to severe chronic low back pain and that the safety profile of BuTrans is consistent with that associated with opioid analgesics and transdermal patches” concluded Steiner.
Source: American Academy of Pain Medicine: www.painmed.org/files/butrans-press-release.pdf
Opioid use can lead to additional sensitivity and pain via opiod-induced hyperalgesia (OIH). Investigators from the Indiana University School of Medicine (IN, USA) have found that the mechanism behind OIH can be hindered by an orphan drug, first used for HIV treatment.
Morphine, although widely used for the control of moderate-to-severe pain, can have serious side effects such as reduced respiration, addiction and constipation, along with potential development of tolerance. Natalie Wilson (Loyola University of Chicago, IL, USA) explains, “In addition to the recognized side effects, morphine actually creates sensitivity and causes more pain through inducing an inflammatory response in the body.”
The mechanism underlying OIH is not very well understood, and along with certain possible underlying major mechanisms, it is thought OIH could be linked with alterations in gene expression.
Owing to increased sensitivity to specific painful stimuli, patients may need higher doses of opioid. Furthermore, declining analgesia during opiod usage may be due, in part, to OIH. Fletcher White (Indiana University) states, “The drug itself is producing its own new pain. I tend to view it as an injury as it appears to be creating another pain.”
Research has suggested that chemokines and the receptors are upregulated through exposure of cells to µ-agonists. Authors write, “recent work from our laboratory implicates chemokine upregulation in a variety of neuropathic pain behaviors.” They go on to comment that in the current research they were able to demonstrate that “mRNA expression of the chemokine, stromal-derived factor-1 (SDF1/CXCL12) is upregulated following morphine treatment in sensory neurons of the rat.”
Amongst other results, investigators reported “pronounced” CXCR4 expression in satellite glial cells in rodents. There was also an increased CXCR4 expression in sensory neurons of the dorsal root ganglion after morphine treatment. The scientists intraperitoneally administered the orphan drug AMD3100, a drug known to block the CXCR4 response, to rats. This totally reversed OIH in the rat. White states, “If this translates appropriately in people, this application would likely make morphine a safer, more effective drug for chronic pain control.”
The authors believe their results suggest that opioid-induced SDF1/CXCR4 signaling is “central to the development of long lasting OIH.” It is hoped that receptor agonists may lead to new ways of dealing with the side effects experienced when using opioids to manage chronic pain.
Sources: Wilson NM, Jung H, Ripsch MS, Miller RJ, White FA: CXCR4 signaling mediates morphine-induced tactile hyperalgesia. Brain Behav. Immun. 25(3), 565–573 (2011); Indiana University School of Medicine News: http://communications.medicine.iu.edu/newsroom/stories/2011/a-safer-more-effective-morphine-may-be-possible-with-indiana-uni
Dara BioSciences Inc. (NC, USA) have announced that a Phase II proof-of-concept study of a new pain medication, KRN5500, has been successful in reducing neuropathic pain. The drug also achieved clinical significance over placebo, an important indicator at this early stage.
Clinical trials evaluating pain medications use subjective pain scores from patients to measure drug efficacy. This gives rise to a high level of ‘background noise‘ in the results, whereby there is more variation in the placebo effect in pain trials. Placebo effect can be as high as 40–50% in some pain trials, making it extremely difficult to evaluate the relative efficacy of an active drug.
Susan Spruill, the study‘s statistician, explained, “The problem is that there is always a placebo response. That‘s because as humans we can manifest a psychological and/or physical response even when there is no real treatment. That effect can‘t be held forever, but we can certainly be tricked for a short period of time. And pain is one of those areas in which we‘re good at tricking ourselves.”
The results presented on KRN5500 at the 2011 International Conference on Accelerating the Development of Enhanced Pain Treatments evaluated 19 patients. Importantly, the placebo response was low, allowing a clearer difference between active- and placebo-treated patients. KRN5500 decreased pain scores by an average of two points from baseline, based on numerical questionnaire ratings; the placebo effect was little or nothing. This met the studies primary end point of reduction in pain from baseline.
The challenge facing the company now will be to design a trial where the placebo effect is again small enough to illustrate the benefit of the study drug. It may be a worry that due to small study size number, the placebo effect was coincidentally low, in which case it will be interesting to see how the study drug fares against more regular levels of placebo effect. Further Phase II trials are expected to begin in the first half of this year.
Source: DARA Biosciences press release: http://phx.corporate-ir.net/phoenix.zhtml?c=219408&p=irol-newsArticle&ID=1543730&highlight=
Recent research published in the Proceedings of the National Academy of Sciences has demonstrated cross-talk between two specific biological pathways could lead to a better understanding of chronic pain.
Bora Inceoglu (University of California Davis Cancer Center, CA, USA) explains, “The interaction of many complex biological pathways is essential for the development of persistent pain, whether inflammatory or neuropathic.” He goes on to say, “Pain is a major health concern and painkiller medications or analgesics do different things.”
The authors of the study highlight the importance of research to better understand pain mechanisms, due to the “side effects and lack of wide-spectrum efficacy of current drugs.” Pain is decreased as natural epoxy-fatty acids (EFAs) are stabilized via inhibition of the soluble epoxide hydrolase (sEH). When there is no underlying painful state, inhibition of this enzyme is not effective. Steven Jinks (University of California Davis School of Medicine) states, “This permits normal pain responses that serve to protect us from tissue damage to remain intact, while alleviating debilitating pain.”
During the investigation, Inceoglu states, “To our surprise, we found that cAMP interacts with natural EFAs and regulates the analgesic or pain activity of sEH inhibitors.” Researchers reported that acute pain in rodents was “dramatically reduced” by simultaneous inhibition of sEH and phosphodiesterase (PDE).
Investigators were able to demonstrate that inhibiting certain PDE isozymes, including PDE4, led to “significant” increases in levels of EFA in a sEH-independent mechanism. The authors suggest “that the efficacy of commercial PDE inhibitors could result in part from increasing EFAs.”
According to Bruce Hammock (University of California Davis Cancer Center) the research is “like something old, something new, something practical and something basic, too.” It is ‘old‘ as the research involves PDE inhibitors – an old class of drugs. It is thought that some of the action of PDE inhibitors is exerted by raising levels of epoxyeicosatrienoic acids. The research is ‘new‘ as the Hammock laboratory has previously reported that epoxyeicosatrienoic acids are increased and stabilized by sEH inhibitors – a new class of experimental drugs.
Hammock explains, “A practical application of this work demonstrated by Bora Inceoglu is that the combination of this old and new class of drugs are highly effective in controlling pain. Of course, the basic aspects of the work include new insights in how epoxyeicosatrienoic acids, cyclic nucleotides and the enzymes that degrade them interact to regulate a variety of biological functions.”
Source: Inceoglu B, Wagner K, Schebb NH et al.: Analgesia mediated by soluble epoxide hydrolase inhibitors is dependent on cAMP. Proc. Natl Acad. Sci. USA 108(12), 5093–5097 (2011).
A continuing prospective study has produced results that suggest that a novel spinal neuromodulation device is effective in reducing lower-back pain in patients who have failed to achieve sufficient control of pain using other spinal cord stimulation methods. The results are from one center of a multicenter trial and were presented at the American Academy of Pain Medicine‘s 27th Annual Meeting. Adnan Al-Kaisy, Clinical Lead of the Pain Management and Neuromodulation Centre, Guy‘s & St Thomas‘ Hospital, London, UK, presented the results of the study.
Results were presented from 30 patients in the study with an average score of eight out of ten on a visual analog scale (VAS) for back pain and six out of ten on a VAS for leg pain.
Initially, approval was obtained from an ethics committee and a trial was completed with success. Following this, dual octapolar percutaneous leads were implanted in the thoracic area of the spinal column; the Nevro Spinal Cord Stimulation was then connected to an implantable pulse generator, which is able to administer waveforms with frequencies of up to 10 kHz.
After 3 months of treatment, the average VAS score for back pain was found to be 2.9 (p < 0.05) and 2.2 for leg pain (p < 0.05). After a further 6 months of treatment, the VAS score for both back and leg pain had decreased to 1.6. Another measure included in the study was the Oswestry Disability Index, which was utilized to assess the affect that back pain had on patients‘ daily lives; at the end of the trial the Oswestry Disability Index was found to decrease from 61 to 44 (p < 0.001).
Commenting on the use of previous spinal cord stimulation systems and the impact of the Nevro system, Al-Kaisy said, “To date there is no evidence that any of these techniques provide persistent long term pain relief at the lower back. Nevro Spinal Cord Stimulation is the cutting edge in implant technology, which certainly is going to make a major difference in the management of persistent lower back pain … Using unique super high frequency stimulation, it suppresses the sparse fibers of the lower back, at the spinal cord level. Moreover, the frequency is so high the patient does not feel ‘the tingling sensation‘ which some patients find extremely uncomfortable and distressing.”
Source: Kaisy A, Smet I, Van Buyten JP: Analgesia of axial low back pain with novel spinal neuromodulation. Presented at: 2011 American Academy of Pain Annual Meeting. Washington, DC, USA, 24–27 March 2011 (Abstract 202).