Lynn R. Webster, MD, FACPM, FASAM
Introduction
The evolving need of pain patients for safe, effective analgesia is driving research into new therapeutic modalities and fresh approaches to familiar treatments. Innovation, involving both opioid and nonopioid pain therapies, dominated discussion at the 23rd Annual Meeting of the American Academy of Pain Medicine held February 7-10 in New Orleans, Louisiana. Because some patients fail to achieve a good outcome with opioid therapy, nonopioid medications and interventions are receiving greater research attention. Opioids are also the subject of new exploration, most of this directed toward separating desired analgesia from unwanted side effects such as euphoria, tolerance, abuse risk, and constipation.
Pros and Cons of Systemic Opioids
A debate titled "Opioids: Good or Bad?" posed a seemingly simple question, then proceeded to prove the answer is most complex.[1] It was suggested that the downside of opioids — including opioid-induced hyperalgesia,[2,3] hormonal suppression, and problems with self-administration — could be attenuated by switching to interventional therapies such as implantable pumps to administer analgesia.
A contrasting view presented during the debate is that systemically-delivered opioids provide safe, effective analgesia with a far lower risk for adverse events than many other medications, including nonsteroidal anti-inflammatory drugs.[1] However, it was emphasized that effective opioid therapy requires careful patient selection, assessment, and monitoring, including a willingness to change course when multiple titrations and rotations achieve no clear benefit.[1]
Nonopioid Alternatives
Cannabinoids
Cannabinoids have demonstrated significant analgesic properties, but problems with side effects remain. Newer compounds show promise for analgesic efficacy while reducing common side effects of dizziness, euphoria, fatigue, and nausea.[4]
An oral mucosal spray (Sativex, GW Pharmaceuticals) that contains 2.7 mg of delta-9-tetrahydrocannabinol (THC) and 2.5 mg of cannabidiol (CBD) has been well tolerated in clinical studies. The co-administration of CBD appears to reduce the psychoactive effects of THC, and intoxication is less than with oral THC, according to presenters at AAPM.[4] Patients are allowed to self-titrate, resulting in an average dose of approximately 20-30 mg/day of both THC and CBD.[5] A double-blind, randomized, placebo-controlled study of 160 outpatients with multiple sclerosis (MS) reported significant reduction of spasticity with the cannabis-based medicinal extract (CBME) (Sativex) compared to placebo (P = .001).[6] A pooled analysis across 3 phase 3 MS spasticity studies, incorporating 666 patients, showed that CBME oral mucosal spray was significantly superior to placebo (P < .05).
The CBME compound has been approved in Canada to treat neuropathic pain generated by MS. Several US clinical trials have been performed, and the US Food and Drug Administration has approved phase 3 studies to evaluate CBME oral mucosal spray in patients with cancer. Obstacles remain to achieving full regulatory and legal approval for cannabis-based medicine in the United States. Eleven states have medical marijuana laws providing patients and caregivers a defense against prosecution; however, federal rulings have created gray areas in how far a practitioner may go to help a patient obtain cannabis.
Spinal Cord Stimulation
Two abstracts emphasized the selective targeting of stimulation sites in therapies utilizing spinal cord stimulation (SCS).
The findings of a prospective, multicenter study support SCS as effective for axial low back pain. Outcome data for 159 subjects who received permanent implants showed significant pain improvement at 3.5 months and at 6- and 12-month evaluation time points (P < .001).[7]
The selective stimulation of sacral nerves proved effective in relieving the pain of 2 women, both of whom had suffered long-time pudendal neuropathy and whose treatment options had been exhausted.[8] The 2 subjects underwent bilateral S3 lead implantation. Both patients achieved excellent relief thereby suggesting that SCS may be an effective option for some patients with pudendal neuropathy.
Targeting Transient Receptor Potential Vanilloid Receptor (TRPV)1 Receptors
Transient receptor potential vanilloid-1 (TRPV1) receptors act as a transducer for heat and low pH (protons).[9] These receptors are plentiful in the skin where they can be activated by trauma and contribute to postoperative pain. Investigational drug 4975 is a long-acting nonopioid analgesic that targets TRPV1 receptors. The drug was shown to be effective for postoperative pain when administered in a single intra-operative dose as part of a multimodal analgesic protocol. Fifty patients who underwent total knee arthroplasty were randomized to receive a single administration of 60 mL of 4975 or placebo along with concomitant preoperative, intraoperative, and postoperative analgesics.[10] The 4975 group reported significantly less pain on first ambulation at day 1 (5.4 vs 7.1 Brief Pain Inventory score) (P = .027) with analgesic benefits at 2 weeks after surgery.
Innovations in Opioid Therapy
Nonselective Opioid Antagonists/Partial Agonists
Fakata and colleagues[11] presented a class review of peripherally acting opioid antagonists. Administered in combination with mu-receptor agonists, opioid antagonists appear to confer benefits for abuse deterrence and analgesia. Some evidence indicates that opioid-induced tolerance and hyperalgesia could be at least partially blocked by the administration of an ultra-low-dose antagonist in combination with mu-receptor agonist therapy.[12] Other agonist/antagonist combinations contain a sustained-release opioid with a sequestered antagonist, such as naltrexone. The antagonist is only released when the product is crushed, damaged, dissolved, mixed with alcohol or water, or otherwise manipulated in an attempt to extract an abusable portion of active ingredient.[13] Taken as directed, the sustained-release action of the opioid remains intact. Although addicted people may still find clever ways to release an abusable portion of opioid, abuse-deterrent formulations may stop some abuse, prevent some overdose deaths, and increase primary-care confidence in opioid prescribing.
Another formulation discussed in the review addresses lack of analgesic efficacy.[11] Patients who fail to achieve lasting analgesia with long-term opioid therapy have achieved benefit using sublingual buprenorphine, a partial mu agonist. The drug was investigated in an open-label study with 95 consecutive patients who were referred by local pain clinics for detoxification from long-term opiate analgesic therapy (mean 8.8 years) due to increasing pain levels, worsening function and — in 8% — opiate addiction.[14] After abstaining from all opiate analgesics for a minimum of 12 hours, patients received low doses of sublingual buprenorphine or buprenorphine/naloxone. The daily sublingual buprenorphine dose ranged from 4 to 16 mg (mean, 8 mg) for an average duration of 8.8 months. Eighty-six percent of patients experienced moderate-to-substantial pain relief, improved mood, and functioning.
Sublingual buprenorphine is approved for opioid detoxification in patients with a primary opioid addiction. Physicians who use buprenorphine for opioid detoxification must be awarded a special license from the US Drug Enforcement Agency.
Peripheral Opioid Antagonists to Reduce Side Effects
Fakata and colleagues[11] also discussed peripheral opioid antagonists designed to reduce side effects. Peripheral effects of opioids include inhibition of small intestine motility, the inhibition of normal colonic movements, and delayed transit, resulting in opioid-induced constipation. Opioid-induced constipation reduces quality of life, increases pain severity, and impairs activities, including work. Two new medications utilize a peripherally acting opioid receptor antagonist that does not cross the blood-brain barrier but directly targets the mechanism of bowel dysfunction to reverse an opioid's effects.
Two phase 3, randomized, double-blind, placebo-controlled trials that enrolled 154 and 133 patients, respectively, showed that subcutaneous methylnaltrexone improved laxation (62% in the first study; 48.4% in the second study) within the first 4 hours of drug administration with no significant changes in pain scores.[15] Median time to laxation was significantly greater (P < .0001) at 0.15 mg/kg (70 minutes in the first study) and 0.30 mg/kg (45 minutes in the second study) compared with placebo (less than 24 hours).
Alvimopan is another peripheral mu antagonist shown to increase gastrointestinal motility and to reduce opioid effects on the gut while demonstrating low systemic absorption. A meta-analysis of 5 randomized-controlled trials compared alvimopan with placebo following bowel resection or hysterectomy.[16] Data were reported on 2195 patients: a total of 1521 (69.3%) received alvimopan and 674 (30.7%) received placebo. The primary efficacy endpoint measures — passage of flatus, stool, and tolerance of solid food — significantly improved with alvimopan as did time to discharge after major surgery.
Side effects of both medications are similar to those of common laxatives and include abdominal cramping, diarrhea, nausea, and flatulence.
Metabolism of Opioids
Metabolism of opioids is influenced by individual genetic variability, a reality that could have implications for the selection and monitoring of pain therapies. Because opioids are metabolized by polymorphic enzymes, including CYP2D6, researchers from the Medical College of Wisconsin undertook a study to evaluate the clinical efficacy of CYP2D6 genotyping for chronic pain patients on analgesic therapy.[17]
Patients were classified as extensive metabolizers, intermediate metabolizers, and poor metabolizers by measuring steady-state opioid concentrations using liquid chromatography/mass spectrometry/mass spectrometry. The higher the steady-state concentrations, the greater the opportunity for adverse drug reactions, according to study investigators. As hypothesized, patients classed as poor metabolizers (5% of the sample) had the highest steady-state opioid concentrations. Of the patients who reported adverse drug reactions, 80% also had impaired CYP2D6 metabolism.
Pharmacogenetic analysis may become more routine to facilitate the selection of treatments and to predict and monitor disease. Genetic profiling also may present ethical issues for purposes of insuring or hiring the individual. These issues have yet to be fully defined and addressed.
Conclusion
Pain medicine will continue to evolve as time and research clarify the risks and benefits of long-term opioid therapy for chronic nonmalignant pain. Heightened patient selection, monitoring measures, and treatment adjustments may increase chances for beneficial outcomes with opioid therapy. Novel opioid formulations, including some that utilize opioid antagonists, may prove valuable for mitigating some opioid-induced side effects. Some patients with pain resistant to systemic opioids or with dose-limiting side effects may require a different route of administration or a nonopioid alternative. Research into cannabinoids as a nonopioid class of analgesia appears promising, but legal and regulatory hurdles remain to the approval of cannabis-derived medicines for pain treatment. Pain treatments and clinical investigations are likely to continue in the direction of nontraditional opioid and nonopioid therapies.
Supported by an independent educational grant from Cephalon
