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PRIORITY PRESS - 28th Annual Meeting of the American Academy of Pain Medicine

Palm Springs, California / February 22-26, 2012

Palm Springs - Effective relief of acute pain is being increasingly recognized as an important defense against the onset of chronic pain. While the traditional focus in patients presenting with an injury and acute pain has been to treat the injury with the expectation pain will resolve, the current paradigm is to treat pain as a separate but related target in a holistic approach. The goal is to prevent a sequence of sensitizing steps that can lead to neuroplastic changes that sustain pain signalling and set the stage for chronic pain syndromes. The concern that masking pain will blunt coping behaviours and encourage dependence on analgesia is not supported by clinical studies. The ability to provide targeted acute pain control may be even greater with newer, better tolerated agents. Based on data presented at the AAPM, newer agents appear to significantly augment pain control options.

Interrupting Pain Pathways

Many of the most sophisticated pain medications are now being developed in immediate- and sustained-release formulations for their very different applications in acute and chronic pain. The goal is not only to provide pain relief but also to interrupt the formation of pain pathways mediated by pro-inflammatory cytokines and the creation of sodium channels that preserve pain signalling even when the stimulus is no longer present.

“Acute pain, if not managed correctly, leads to chronic pain. We now understand that the chronic pain syndromes which develop in patients with an acute injury are disease processes in themselves,” reported Dr. Chester C. Buckenmaier, Walter Reed Army Medical Center, Washington, D.C. Citing research partly based on new approaches to controlling acute pain in soldiers wounded in Afghanistan and Iraq, he observed that the major advance over the past decade has been the movement away from unrestricted use of morphine to far more targeted strategies.

“Anyone can prescribe morphine, but this is treatment of the pain and the more important approach is to treat the patient,” Dr. Andre P. Boezaart, Department of Anesthesiology, University of Florida, Gainesville, told delegates. He indicated that newer, immediate-release (IR) agents employed in conjunction with exercise and therapy for the underlying source of pain substantially increase the likelihood of a full recovery.

Of the newer medicines, several have been associated with a high rate of efficacy and a lower abuse potential than morphine, oxycodone and other older agents. These include 2 new opioid antagonists, the recently approved tapentadol and NKTR-181.

Advances in Acute Pain Control

The goal of effective acute pain control is focused therapy for a limited period, preventing formation of pain pathways that persist even after the acute injury has resolved. As a centrally acting agent, tapentadol provides pain control via 2 pain pathways in 1 molecule. The first is mu-opioid receptor agonism, and the second as a norepinephrine (NE) reuptake inhibitor, providing a second pathway of pain control.

In phase III data presented at the AAPM, 585 patients were randomized to IR formulations of either tapentadol or oxycodone. Findings on the advantages of IR tapentadol relative to IR oxycodone are compelling.

The groups were divided into 2 strata of which the first was composed of those with Quebec Task Force Classification (QTFC) category 3 acute low back pain and pain radiating below the knee. The second was composed of patients with QTFC 4 (demonstrating neurological findings) and QTFC 6 (evidence of nerve compression on imaging) low back pain. Patients were initiated on IR tapentadol 50 mg or IR oxycodone 5 mg q4-6 hours and allowed to titrate up (to a maximum IR tapentadol 100 mg or IR oxycodone 15 mg) after the first day to achieve pain relief.

There were essentially no differences between groups in either strata for the primary end point, which was sum of pain intensity differences (SPID) at day 5. There were also no differences in SPID when the treatment arms were compared at days 2 and 3. However, there were substantial differences in adverse events. This included rates of gastrointestinal (GI) disorders overall (29.4% vs. 43.2%) and specific GI events, such as nausea (15.9% vs. 20.7%), vomiting (15.9% vs. 24.7%) and constipation (2.2% vs. 7.1%) for tapentadol and oxycodone, respectively. Rates of pruritus (8.4% vs. 8.0%), dizziness (11.8% vs. 10.5%), somnolence (8.1% vs. 6.8%) and headache (4.4% vs. 6.2%) were similar (Table 1).

Table 1.

Reducing Uptake Rate and Adverse Events

“Opioid-related side effects pose significant challenges for managing moderate to severe pain,” reported Dr. Bill McCarberg, Kaiser Permanente, San Diego, California. As senior author of this study, he indicated that these and other concerns over promoting dependence on pain medications can lead to inadequate pain control, which is a fundamental issue in the sustained pain that can generate chronic pain syndromes.

Attempting to improve pain control without increasing the types of adverse events that interfere with compliance is also driving novel treatment development. The strategy employed by another opioid-related agent has been to slow the rate of uptake of the active drug into the central nervous system (CNS).

In data presented at the AAPM, NKTR-181, a mu-opioid-receptor agonist, appears to preserve its analgesia in the periphery with low abuse liability in experimental studies. The animal data demonstrating slow CNS uptake has been confirmed by phase I clinical data. In addition, the phase I data showed promising degrees of tolerability consistent with a slow CNS uptake.

“NKTR-181 was well tolerated over the entire 8-day dosing period at all doses evaluated and there were no serious adverse events encountered. The most frequent adverse events at the highest doses were those common to opioid agonists, including nausea and constipation,” reported Dr. Lynn Webster, Lifetree Clinical Research, Salt Lake City, Utah. He reported that based on a tenfold slower CNS uptake relative to oxycodone, it may have major advantages in preserving pain control with a reduced risk of the CNS side effects, such as somnolence and dizziness, that affect drugs in this class.

Simpler Regimens, Less Bother

One of the advantages of a reduced risk of side effects is that it permits simpler analgesic regimens, according to another set of data presented at the AAPM. In this analysis, a survey was undertaken in 630 patients taking hydrocodone and 601 patients taking IR oxycodone. Nearly half of the patients in both groups were taking the opioid to control acute back or neck pain. The survey specifically inquired about side effects associated with the medication and the use of other analgesics, such as acetaminophen, ibuprofen and ASA, when side effects were present.

“More oxycodone respondents were bothered by 1 or more side effects (84.0% vs. 67.3%) overall and more were very bothered (30.8% vs. 26.0%),” reported clinical researcher Kathryn P. Anastassopoulos, Covance Market Access Services, Gaithersburg, Maryland. More importantly, however, there was a tight correlation between being bothered by side effects and increased use of adjunctive pain medications whether patients were taking oxycodone or hydrocodone.

“As the bother caused by side effects [due to opioids] increased, other medication use increased, levying economic and potential clinical burden on respondents,” Ms. Anastassopoulos reported. Moreover, she indicated that these complications can draw focus away from a holistic strategy of targeted pain control within the context of exercise and rehabilitation that can accelerate recovery as the injury resolves.

Summary

New options for analgesia fit well with the emerging paradigm of treating rather than simply controlling acute pain. Newer agents such as IR tapentadol with lower rate of side effects and a rapid analgesic effect permit patients to focus on recovery rather than pain and lend themselves to the exercise and rehabilitation that should be part of a holistic approach to pain management. While concern about the risks of earlier-generation opioid agonists often led to inadequate doses and early discontinuation of therapy, increasing risk of sustained pain and chronic pain syndromes, newer agents fit well with a paradigm of targeted treatment with a rapid onset.