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Study Finds Opioids [including Levorphanol] Offer Significant Reduction in Nerve-Damage Pain

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Attempting to resolve a long-standing controversy, UCSF researchers have shown that people suffering from chronic pain due to nervous system damage – known as neuropathic pain — improved significantly after an eight-week course of the morphine-like medication levorphanol. Neuropathic pain affects about three million people in the U.S., and is considered very difficult to treat.

Physicians have been reluctant to prescribe opioids for their patients with neuropathic pain because of concerns about ineffectiveness, addiction, and side effects. Animal studies have shown opioids to be relatively ineffective when the nervous system is damaged, and loss of pain relief over time (known as tolerance) develops quickly.

The new study, in contrast, found that levorphanol’s ability to reduce pain was comparable to that of tricyclic antidepressants and the anticonvulsant gabapentin, two commonly used drugs for neuropathic pain treatment. This is the first double-blind comparison of two dose levels of opioids for the full range of neuropathic pain conditions, the researchers note.

The study found that high-dose treatment provided much greater pain reduction than a lower-dose regimen. Patients did not become tolerant of the drug — continuing to increase their dosage.

However, the researchers did find that more people in the high-dose group dropped out of the study, complaining of a range of side effects, including restlessness, depression and behavior changes. Participants who dropped out with symptoms of increased anger, irritability, confusion or mood and personality changes were on the higher-dose regime.

“The study shows that opioids can be beneficial for relief of neuropathic pain, but don’t help everyone,” said Michael Rowbotham, MD, Professor of Clinical Neurology and Anesthesia at UCSF and Director of UCSF’s Pain Clinical Research Center. “The benefits must be weighed against the drawbacks for each patient. Some may take a dose high enough to produce many side effects, but still experience no relief of their pain.”

Rowbotham is lead author on a paper in The New England Journal of Medicine reporting the findings. An editorial in the journal also highlights the study.

The researchers found that opioids may be less useful for those with pain from damage to the brain (central pain) due to stroke or brain lesions. Seven of the ten people with central pain from these causes dropped out of the study. But the high-strength capsules proved particularly beneficial to those with central pain from spinal cord injury or multiple sclerosis. Patients with damage to peripheral nerves, such as postherpetic neuralgia following shingles, peripheral neuropathy such as from diabetes, and localized nerve injury also reported substantial reduction in pain.

The study involved 81 patients, 59 of whom completed the eight-week therapy with the drug levorphanol. All patients had severe and long-lasting pain, and at least one failed attempt to control their pain with non-opioid drugs. Patients were prescribed either the low-dose or high-dose medication without knowing which they had received. They were encouraged to find the optimal balance between pain reduction and side effects within a certain maximum number of capsules per day – ranging from three per day during the first week, and topping out at 21 capsules per day from weeks four through eight. Despite this “patient-friendly” regime, 27 percent of participants dropped out of the study.

Patients on the high-strength dosage took a mean dose of 8.9 mg per day, while those on the low-strength capsules took a mean dose of 2.7 mg per day. The degree of pain reduction was significantly greater in the high-strength group, with an average of 36 percent reduction on a standard scale, compared with a 21 percent reduction in the low-strength group.

To firmly prove that opioids relive neuropathic pain, a placebo would be required for comparison. But no placebo was used, since opioids have distinctive side effects and patients would know whether they were taking the opioid or the placebo, Rowbotham said. In addition, it would be difficult to completely withhold opioids for this group of participants with severe chronic pain because opioids are not considered an experimental treatment for chronic pain.

Nonetheless, the significant differences between the two dosages and the fact that the patients returned to pre-study pain levels after the treatment, “strongly suggest that higher-dose opioids effectively reduce the intensity of chronic neuropathic pain,” the authors conclude.

UCSF co-authors on the paper are Lisa Twilling, PhD; Pamela Davies, MS; Kirk Taylor, MD; David Mohr, PhD, all at UCSF’s Pain Clinical Research Center at the time of the study; and Lori Reisner, PharmD, associate clinical professor of clinical pharmacy at UCSF.

The research was funded by the National Institutes of Health.

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