Publications
APS Bulletin • Volume 17, Number 2, 2007
Research Update
Norman Harden, MD, Department Editor
Where’s the Long-Term in Opioid Research?
Jane Martinsons, Staff Writer
Collisions tend to spur questions and nowhere is that more evident than with opioids where there’s a collision of minds over how best to treat noncancer chronic pain (NCCP) patients without increasing their risk of abuse or addiction. Toss in the fact that both the rate of abuse and the number of opioid prescriptions continue to climb nationwide, and questions abound. Here, for example, are what a few pain experts say are their top concerns with opioid therapy:
What’s the risk of prescribing opioids to a patient who may abuse, divert, or become addicted to these medications, and will that lead to undertreating NCCP patients who are unlikely to abuse opioids?
How do you determine who’s at risk of abuse? Are physicians’ judgments on risk reliable? Should physicians select patients for treatment to minimize behavioral problems? Is that ethical?
How do you measure pain reduction, as well as mood and function improvement? Do opioids actually provide pain relief and improve functionality and quality of life?
Should ceilings on doses be instituted?
Does continuous use of opioids compromise the ability to treat new onset pain?
Does opioid tolerance wear off with time?
With more than half of NCCP patients on opioids having hypogonadism, why isn’t more being done on the part of the Federal Drug Administration (FDA), pharmaceutical companies, and the National Institutes of Health (NIH) to study the condition and its impact on pain control and treatment?
Can abuse-deterrent formulations impact the problem of prescription drug abuse?
Will rapid-onset opioids get used—and used safely?
How do we treat negative side effects associated with opioid use, which may include constipation, hypogonadism, hyperanalgesia, increased susceptibility of infection, and even increased risk of death?
Long-Term, Human Trials Needed
And this is just a sample of concerns. Still, most experts who recently spoke to APS Bulletin contend that the core issue around which all these questions revolve is the lack of longterm or human data on opioid therapy.
“The greatest controversy is what is the long-term safety and efficacy of chronic opioid therapy in patients with nonmalignant pain. Do they work? How long do they work for? Who is the right candidate for it?” says Kathleen Foley, MD, of Memorial Sloan-Kettering Cancer Center in New York. “What surrounds this whole issue is we don’t have good data,” she says, and “we don’t have any long-term trials.”
Foley stresses that concerns over addiction may only serve to co-opt discussions over much needed research, and may even divert new monies away from finding better drugs and advancing the scientific basis for pain treatment.
Other pain experts say that the studies that do exist are either flawed or are short-term trials that don’t address long-term use of opioids for chronic pain. Gilbert Fanciullo, MD MS, of Dartmouth Hitchcock Medical Center in Lebanon, NH, says that the dozen or so often-cited “big” studies demonstrating that opioids are useful for NCCP are “seriously flawed” and leave open the queston of whether opioids provide long-term benefits.
Meanwhile, Dennis Turk, PhD, of the University of Washington in Seattle, says that most studies are 35-day randomized controlled trials conducted by pharmaceutical firms that base their research on their own agenda. Frequently these studies exclude people believed to at high risk for abuse or are beset by high participant drop-out rates because of the negative side effects associated with taking opioids.
“Although randomized studies are supposed to be so-called ‘gold standard,’ in the case of chronic opioid therapy they have a limited role because you can only conduct them at months at the most, usually weeks,” says Jane Ballantyne, MD, MGH Pain Center in Boston. “They don’t really tell you what’s happening either in the long term or in the wider population.” Ballantyne points out that some research currently underway includes broader epidemiological studies that, unlike smaller studies, are showing that opioid-treated patients do not fare as well, or fare worse, than nonopioid-treated patients in terms of pain, quality of life, and function.
Others say the focus should be on clinical trials rather than lab trials. Nathaniel Katz, MD MS, of Analgesic Research in Needham, MA, and Tufts University in Boston, says that for the past 50 years research has been conducted “completely in the wrong direction,” with laboratory studies driving clinical research instead of the other way around. However, he adds that initiatives such as the NIH Roadmap, FDA’s Critical Path Initiative, and APS’s Translational Research Task Force could help reverse the trend and lead to the development of more effective and safe therapies.
What’s needed are “naturalistic studies so that you get around some of the immense problems of selection bias in the existing opioid literature,” says Steve Passik, PhD, of Sloan-Kettering, who acknowledges that finding funding for such studies poses a challenge. He contends that these studies would involve “real time patients treated by real time doctors,” with study participants who show signs of substance abuse either going off-study or receiving structured management.
Lack of Funding
But several pain experts say that the real heart of the issue is the underfunding of pain research. “NIH and other agencies just have not prioritized pain as an issue strongly enough,” says Fanciullo.
Katz says that a “huge part of the problem has been the lack of adequate funding by any of the stakeholders of research on the fundamental and critical questions regarding prescription opioid abuse. If you peel away all the layers [of this issue], the final nucleus of all these problems comes down to the same thing—effective advocacy of key policy makers at a federal level. NIH and the FDA have not yet demonstrated that they will foster the necessary clinical research, suggesting that policy approaches may be needed. If you can’t get it funded, it isn’t going to happen.” Both Katz and Fanciullo are hopeful that the funding outlook will improve with APS’s current lobby efforts and position statements. At the APS Annual Meeting in May, board members visited their representatives in the House and Senate to discuss APS’s legislative agenda. Details of this agenda can be found on the APS Web site at www.ampainsoc.org/advocacy/ legislative.htm.
Meanwhile, APS and the American Academy of Pain Medicine are developing opioid guidelines to develop specific, actionable recommendations for clinicians to optimally manage their patients. Draft recommendations are slated for release in August and final recommendations are expected by year’s end.
Upcoming Trends
What can we expect in long-term opioid therapy in the next 1 to 3 years? These experts say that we’ll see more focus on:
Objective measures of pain and risk of abuse
Increasingly, objective measures like urine toxicology screenings are revealing just how unreliable clinicians are at judging who’s at risk for addiction and abuse, Turk says. Upwards of 40% of patients taking opioids are not doing so as prescribed, either by not taking them, taking too much of them, or taking them in combination with other drugs, he says.
However, several initiatives are underway to develop objective measures to assess that risk. Among them is the patient questionnaire. Fanciullo is one of a handful of pain physicians who have patients fill out an extensive questionnaire—in his practice, using a computer touchpad. He also uses a variety of tools to measure patients’ pain and display these scores graphically. “Let’s say I’m prescribing an opioid to my patient for 7 months,” he says. “That’s all I have to do is glance at graphs to see if a patient’s pain has diminished or if their function has improved. It takes me 5 seconds using validated instruments. It’s extremely useful. We can show it to the patients and say, ‘Look, you think you feel better, but this is what this shows.’”
According to Katz, there is a growing awareness that opioids cannot be prescribed safely without external outcomes measures, including urine toxicology screening and prescription monitoring. He says that prescription monitoring is likely to be particularly useful because it allows practitioners to increase access to opioids for those who do well on therapy, and reduce it for those who don’t.
Abuse-deterrent opioids
Look for more studies on reducing the abuse potential of existing opioids. Turk predicts more systematic human studies on hyperalgesia to identify whether it’s a significant problem and, if so, how to measure and assess it.
Likewise, Ballantyne says that basic science research will provide “further insight into the neuroadaptations that underpin the clinical phenomena of opioid tolerance, hyperalgesia, dependence, and addiction.” This, she says, “may open up the possibility of pharmacological manipulations to alter these adaptations and reduce their adverse clinical consequences.” Ballantyne says also to expect advances in genetics to tailor opioids to people’s unique metabolic and psychological makeup.
Passik, meanwhile, acknowledges that abuse-deterrent opioids will help reduce prescription drug abuse, but cautions that pain doctors receive intensive medical education on addiction medicine. “Relying on the drug delivery system to substitute for getting more savvy about addiction medicine could lull people into a false sense of security,” he says. “Ultimately someone will figure out how to tamper with them, and it will blow up in our faces.”
Combination therapies
Look for more focus on using opioids in combination with other medications, such as anticonvulsants, or in conjunction with physical or psychological therapies. Several pain physicians expect that, as a consequence, open-ended dose escalation of a particular opioid for chronic pain management may be on the way out.
Increased scrutiny of potential patients
Expect ethical concerns to mount in coming years as physicians continue to grapple with determining which patients are good candidates for opioid therapy. Not only will there be more emphasis placed on finding validated screening instruments, but physicians may face the prospect of having to select patients for treatment, Ballantyne says.
On the flip side, Passik foresees the spread of a mass media ad campaign to educate consumers on how to properly store and monitor their drugs, including opioids. Either way, clinicians will be looking at ways to avoid the head-on collision between patients and the wall of addiction.