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New Research Findings in Chronic Pain

Chronic Pain - Medical Conditions, Health, and Mental Health: New Research Findings in Chronic Pain: An Expert Interview With Frederick W. Burgess, MD, PhD 03/08/2007 Editor's Note: The American ...

 

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    New Research Findings in Chronic Pain

    New Research Findings in Chronic Pain: An Expert Interview With Frederick W. Burgess, MD, PhD
    03/08/2007

    Editor's Note:
    The American Academy of Pain Medicine 23rd Annual Meeting took place from February 7 to 10, 2007 in New Orleans, Louisiana. During this meeting, new information about the diagnosis and treatment of pain disorders was presented. Marni Kelman, MSc, Medscape Neurology & Neurosurgery Editorial Director, discussed results presented at this year's meeting and their implications with Frederick W. Burgess, MD, PhD, Clinical Associate Professor of Surgery (Anesthesiology), Brown University, The Warren Alpert Medical School, Providence, Rhode Island; Attending Anesthesiologist, Rhode Island Hospital, Providence, Rhode Island.

    Medscape: In your opinion, what were the most important research findings presented at the meeting this year?

    Dr. Burgess: The 2007 meeting provided a diverse overview of topics ranging from opioid prescribing, opioid addiction, neuromodulation, to the recognition and management of complications arising from interventional procedures. In terms of significant research findings, several poster presentations provided some interesting insights into current pain issues. Eriator and colleagues[1] presented the results of a community survey on the perception and response to warning signs of inappropriate prescription drug use. Their data demonstrated that the public regards cocaine as the predominant drug abuse problem. Although current government statistics show that prescription opioids are the leading substance abuse problem, contributing to more accidental overdose deaths than cocaine and heroin combined, only 9% of the survey participants viewed prescription drug abuse as a major problem. Of interest, 50% of the respondents claimed a direct family exposure to the use of illegal drugs.

    Another interesting report by Wasan and colleagues[2] examined the value of several screening tests as predictors of aberrant drug-related behavior among patients with chronic pain. Their findings showed that psychiatric factors, including a history of mood disorder, psychological problems, and psychosocial stressors, are associated with a greater likelihood of testing positive on urinary drug screening, and significantly higher scores on the Aberrant Drug Behavior Index. It is unlikely that any specific screening test will routinely predict which patient will display aberrant drug behavior, but such screening may facilitate early recognition and aid monitoring of patients at risk.

    In recent years, pain specialists have become quite aggressive in using opioid medications to manage chronic non-cancer-related pain conditions, and this has created considerable concern among state and federal regulatory agencies. Primary care physicians have been noted to be much less likely to prescribe potent long-term opioid therapy for noncancer pain conditions for fear of abuse, diversion, and harm.[3] This critical attitude surrounding the use of chronic opiate treatment arises from concerns over the escalating incidence of prescription drug abuse and the potential for drug diversion and abuse associated with the increasing availability of opioid medication within the community. It remains unclear whether appropriate opioid prescribing contributes to this problem. Nevertheless, physicians must take great pains to carefully evaluate, monitor, and document their opioid prescribing.

    An interesting study that appeared in the poster session presented a survey of patients in methadone treatment programs. The goal of the study was to identify the source of illegal prescription drugs obtained by the patients.[4] Their data were interesting in that the majority of the survey participants reported obtaining their abused prescription medications from "dealers" and friends or family members. Physicians accounted for a substantially smaller percentage (30%) of abused prescription drugs, and the Internet for even less -- contrary to widely held impressions. Exactly where the drug dealers get their opioid medication is still a major question. There have been reports of theft of controlled drugs from various sources in the supply chain, extending from the manufacturer, the pharmacist, and to the patient. The important point here is the fact that physician-prescribed opioids are not necessarily the primary source of diverted prescription opioids. There are glaring exceptions to this statement, but overall, most physicians prescribe opioid medication in a thoughtful and appropriate fashion, as witnessed by the small number of doctors prosecuted or penalized by regulatory agencies.

    A session conducted by Drs. Howard Heit, Edward Covington, and Douglas Gourlay,[5] which focused on the interface of pain and addiction, is also important to mention. The presentations addressed the full scope of issues involved in prescribing opioids to pain patients with attention to monitoring for addictive behavior, how to screen patients for aberrant behavior, and how to cope with failed treatment situations. The issue was debated again in another session,[6] during which it was suggested that we may have gone too far in our management of pain with high-potency opioids. Many pain specialists faced with treating someone in pain, without a clear etiology for the pain, will often explore a variety of empiric medication trials. If this approach fails, there is a tendency to resort to prescribing a potent opioid. Unfortunately, there is mounting evidence that suggests that the opioids, perhaps our most effective analgesic class, are not universally effective and may be associated with poorer outcomes over the long term. Prior to 10 years ago, it was a generally accepted approach to treat chronic noncancer pain by eliminating opioid treatment and wean everyone off their opioid medication. Over the last 10-12 years, there has been a push to be more aggressive with opioids. Now we are finding that perhaps we went a little too far and that opioids are not the panacea for everyone. There continues to be considerable debate on this topic, and some specialists believe that we should be much more selective in employing opioids. It should not be a knee jerk reflex that if someone has pain that an opioid is always the best and final solution. The belief is that we need to focus on many of the other treatments that we have used in the past, such as rehabilitative approaches, cognitive-behavioral therapy, and other types of nonopioid analgesics (such as NSAIDs [nonsteroidal anti-inflammatory drugs] or tricyclic antidepressants), to individualize therapy as much as possible. Unfortunately, in recent years many barriers to comprehensive pain treatment have evolved, leading to a greater reliance on opioid medication.

    Another area that I want to mention is the information pertaining to neuromodulation. There were several sessions on this topic. Dr. Joshua Prager[7] gave an excellent review of the field in his "Decade of Pain Lecture: Four Decades of Neuromodulation" concerning what we have been evolving from and to with neuromodulation. Rather dramatic results have been seen with neuromodulation techniques in the treatment of Parkinson's disease with deep brain stimulation, radicular and low back pain, and for the management of refractory major depression. One of the areas that is of considerable interest to many pain specialists is the evolving role of neuromodulation in the management of visceral pain syndromes. Although there are still not a lot of hard, randomized controlled trial data on the use of neuromodulation for visceral pain, such as for problems involving the intestines, stomach, and pelvic organs, mounting case study evidence suggests a valuable role for neuromodulation in this area. Various case reports have been presented showing that neuromodulation may be successfully applied in the treatment of abdominal pain and for pain associated with the genitourinary tract where more traditional analgesic treatments have been unsuccessful.[8,9] Dr. Kapural reported on a series of 6 patients with chronic pelvic visceral pain treated with spinal cord stimulation and followed them for a mean period of 30 months. The average pain score decreased from an 8 to a 3, with all patients reporting a minimum reduction in pain of 50%. Opioid consumption was reduced on average by two thirds.[8,9] That was pretty interesting because it counters what we originally thought.

    Medscape: What about addiction, another important topic? Was anything presented on this topic that was important?

    Dr. Burgess: As noted above, one of the premeeting conferences, "The Truth about Pain Management: The Interface of Pain and Addiction," provided a well-balanced examination of this issue.[5] Dr. Heit presented a nice overview on current theories on addiction and the overlap with pain practice. Dr. Gourlay then introduced the concept of "Universal Precautions" in pain medicine. This strategy is designed to implement a well-thought-out plan designed around careful assessment, ongoing evaluation, establishing clear lines of communication and boundaries between the patient and the prescribing physician, and careful documentation. It is extremely important for the treating physician to create a transparent record that will allow regulatory agencies to clearly see the thoughtful consideration that went into the decision-making process, and to exhibit a system of careful controls. I think many physicians believe that their only concern needs to be that they are addressing the patients' pain, so if their patients become involved in illicit or medication issues, some argue that it is not their problem. This is a rather narrow-minded view that fails to take into account the physicians' responsibility to protect the general public health affected by prescription drug diversion,[10] and I believe that most of the state medical boards agree. What we are seeing is a greater emphasis being placed on evaluating patients for addiction/diversion, with the responsibility for monitoring them closely falling to the prescribing physician.

    When you look at chronic pain populations, low back pain is a major issue for most pain specialists. Published data suggest that more than one quarter of these patients may exhibit some drug abuse/misuse behavior at times. This indicates that we need to be more attentive and take steps to try and guard against inappropriate diversion or the misuse of medications. Some of those measures tie into prescribing practices, and others tie into the issue that perhaps it should become a standard monitoring technique to send every patient for routine drug urine screening, to look for evidence of substance abuse, and to assess patients to make sure that they are actually taking the medication that you are prescribing.

    There are a lot of recommendations and discussions on how to monitor these patients, and whether you should be screening everyone vs setting up a protocol to target high-risk individuals varies with each expert. Screening for certain behavioral patterns and coexisting psychological disorders can be helpful in establishing monitoring standards and in raising warning flags. There is some debate as to what to do with the average patient for whom you do not suspect of aberrant drug behavior. Data suggest that 20% or more of those patients could be involved in illicit activity with the drugs, whether it be diversion or abuse. This suggests that perhaps everyone should be randomly screened at least once a year.

    Medscape: What about steps you can implement up front, such as treatment agreements?

    Dr. Burgess: Treatment agreements are generally regarded as being a standard measure for prescribing opioids, as outlined in Dr. Gourlay's presentation noted above.[5] The American Academy of Pain Medicine has useful templates for a patient opioid treatment agreement on the Web site (painmed.org) that may be given to the patient, to serve as both a consent form and an advisory form with the rules and issues involved with controlled substance prescribing. In my own practice, I have a standard form that I have every patient receiving opioid therapy review and sign, and then I give them a copy and I keep the signed copy in their chart. I regard an opioid agreement to be documentation of the boundaries that have been established with each patient, and as a means of documenting their understanding or the risks and requirements associated with continued opioid therapy. They do not serve as a formal contract, but more as a valuable education tool. However, you have to be cautious not to be overly restrictive to avoid creating unintended liability traps. For example, if you have a patient who screens positive for marijuana use in their urine drug screen, should this be a sufficient trigger to withdraw therapy? There is a debate about what to do with this information. It is essential to really think about these issues and establish protocols to deal with the results of urine screens ahead of time, before you start screening. Failure to do so will create possible legal liability.

    Medscape: Do you find that this information is widely known by all physicians?

    Dr. Burgess: Most pain physicians are fairly knowledgeable in this area. I think where we have problems is with primary care physicians who are prescribing opioids. Many pain specialty clinics, especially many of the academic centers, will not take over the opioid-prescribing responsibilities for the patient. They will actually propose a treatment plan and send the patient back to the primary care physician for continued management and prescribing. Because a lot of these physicians are not extensively trained or focused in the area of pain management, they may not be as aware of the issues. I think a lot of physicians get into trouble with regulatory agencies, despite having the best intentions. The doctor who is most often prosecuted by a state medical board is the primary care doctor working in a rural environment who is trusting of his/her patients and tends to take the attitude of trying to relieve suffering, and trying to do the right thing. Unfortunately, these doctors can be taken advantage of because they do not have well-developed policies and procedures in place to deal with the complicated pain patient.

    Medscape: Is the solution to provide more medical training and/or continuing medical education, or is it for these physicians to refer patients to somebody else who may know more?

    Dr. Burgess: I think it is debatable. We have seen it go both ways. For example, in Washington state they are working on a law that would require a primary care physician to engage a pain management specialist to monitor the patient along with you to guide their therapy when the average daily dose exceeds 120 mg of morphine. If you look at most of the guidelines that have been promoted by state medical boards, they always indicate that you have to consult with the appropriate specialist. You want to show that you made a good faith effort to do the right thing and that you involved people who have the knowledge to deal with these issues to support your treatment practice.

    Part of the problem is that in medical school there is so much to teach that it is very hard to fit all the required medical education into a manageable 4-year curriculum. At most medical schools, only a very small amount of pain education is incorporated into the medical student's education. The state of California has made an effort to require 12 hours of pain education in medical school training; however, enforcement and monitoring of this requirement are not well developed. The other aspect is that students do not often understand the significance of what they are learning at the time. For example, a student may learn about drug diversion issues and analgesic pharmacology, but they do not have the clinical experience to frame the material. I think this type of training should be incorporated at the residency training level in the form of an organized curriculum.

    For the practicing primary care physician, there is considerable need for pain education encompassing pain assessment, drug selection, and training in how to counsel and monitor patients prescribed potent opioids. Many states have instituted continuing medical education requirements for physicians. Although I am not an advocate for greater mandatory regulatory burdens, the current crisis of poorly managed pain and escalating prescription drug diversion may obviate the need for a standardized educational approach.

    Medscape: Can you think of other unmet needs that you believe exist in chronic pain management that should be addressed in the future?

    Dr. Burgess: We have learned a lot about pain and pain pathways, but there is still more to learn. One of the biggest things that we are lacking in pain medicine are randomized controlled studies that answer a lot of the questions that we are facing. In looking at the abstracts from the meeting this year, a lot of the studies that were presented were limited case studies. The difficulty with case studies is that pain symptoms have a tendency to spontaneously resolve in time, and there is a substantial placebo effect with all types of intervention. Oftentimes we are using treatments that are unproven, but become widely adopted, only to be proven ineffective on closer inspection. My impression is that we need to develop well-controlled randomized trials to provide the level of evidence necessary to make confident treatment decisions. The difficulty in accomplishing this goal is related to inadequate funding for research and the inherent difficulty in objectively measuring pain.

    Medscape: Were there any drugs in development or new techniques discussed at the meeting that you believe are particularly promising?

    Dr. Burgess: One area that I think is extremely promising, but is still in its infancy, was discussed in a session called "Breaking Concepts in Diagnosis and Treatment of Complex Regional Pain Syndromes.[11]" This topic focused on the use of functional brain imaging to look for areas of the brain that are active in response to pain stimuli. This new technology is still in a very early stage, but holds great promise for enhancing our understanding of how the brain processes pain. Functional brain imaging may represent an excellent opportunity to provide an objective measurement of pain and provide a means to monitor treatment efficacy. Preliminary data suggest that we can see distinct alterations in neurologic patterns associated with various stimuli in patients suffering with complex regional pain syndromes.

    Medscape: Have any of the studies using functional MRI investigated the effects of a particular drug?

    Dr. Burgess: These studies are currently under way. Unfortunately, this technology requires a great deal of time and financial support. Magnetic resonance imaging is a cumbersome method of collecting data on large patient populations. The preliminary data suggest that we definitely do see differences in patients compared with control populations, and it appears that sometimes symptoms resolve back to normal or near normal with treatment. The problem in interpreting current results is that the control standards have not been clearly established. Most of these studies have been conducted in normal controls vs chronic pain patients, which may not be adequate as controls. Further studies are needed to elucidate the differences in acute and chronic pain states. In addition, the impact of psychological illness on sensory brain activity and information processing will also need to be examined. What this technology does is let us look a little more closely at some of the neurologic processes involved in pain. It will be a little while longer before we get hard results, but it is a promising direction.

    Medscape: Is there anything else you would like to mention in regard to results presented at the meeting?

    Dr. Burgess: One important issue that was discussed is the aspect of disability in pain. When you look at patients who are going out on disability from work, typically the disability is due to a pain-related problem for the majority of patients. Many patients have disability due to pain associated with poorly defined anatomic injuries. Physicians are frequently tasked with trying to determine the legitimacy of the patients' disability and to rate their impairment. By definition, pain is a subjective complaint, for which we have labored to find more objective measures. The variability in the intensity of pain associated with a defined anatomic injury frequently runs a broad spectrum. Why should one individual experience minimal discomfort following a lumbar discectomy, while another is unable to stand or walk? Recent basic research into the genetic and biochemical etiology of pain has offered some insight into this question.

    Results from a recent biochemical study[12] suggested that a portion of the population may be predisposed toward developing chronic pain. The study authors showed that GTP cyclohydrolase (GCH) 1, the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis, is a key modulator of peripheral neuropathic and inflammatory pain. Inhibiting BH4 synthesis in rats attenuated neuropathic and inflammatory pain, while administering BH4 exacerbated pain. Of note, in humans, a specific haplotype of the GCH1 gene was significantly associated with reduced pain following discectomy for persistent radicular low back pain, comparing favorably to the data generated from the animal model.

    The average person who has a disc removed from his/her back may do very well, and there is no evidence of a problem. However, some patients do not get better and have continued pain. It could be that these patients are genetically susceptible, so they experience persistent pain. Results such as these suggest that some patients may have a predisposition to chronic pain that is beyond their control, which will need to be addressed in a different manner. Identifying genetic predispositions or the presence of pain activity in the brain with functional MRI may be able to help determine whether patients have real pain and disability. This highlights the potential value of imaging of the brain to help learn more about pain and its treatment.

    Another important topic discussed is the use of cannabinoids for pain management.[13] In total, 11 states have approved the use of medical marijuana for the treatment of chronic pain or for nausea associated with chemotherapy. The medical community has lagged behind a bit and partly because there are really very little, quality, controlled clinical data with cannabinoids. Restricted legal access to Schedule I drugs, such as marijuana, tends to hamper research in this area. It is also very hard to do controlled studies with a drug that is psychoactive because it is hard to blind these effects. It is similarly difficult to do studies with opioid analgesics; as it is difficult to come up with a control population in which you can fool patients into not knowing which drug they are getting.

    The two major issues with medical marijuana were discussed. One is that there are just not a lot of good solid clinical data. Some animal data definitely provide clear evidence for cannabinoid receptors producing a modulating effect on pain and nausea. However, human studies are more anecdotal, and most reports are uncontrolled and simply descriptive. It is hard to come forward as a medical professional and say that we should use this treatment without good evidence. This is the problem that the American Academy of Pain Medicine and many other medical specialty societies have faced in approaching the medical marijuana issue. In this age of "evidence-based medicine," organized medicine finds it difficult to promote untested treatments. It is difficult to justify advising our patients to smoke street-grade marijuana, presuming that they will experience benefit, when they may also be harmed. One of the conclusions that came out of our discussions is that we would like to see greater emphasis and support from the government to evaluate medical marijuana further and allow legitimate testing. At the present time, you can only get research-grade marijuana or THC [delta-9-tetrahydrocannabinol] from one location, which leads to the belief that this restricts the development of a greater understanding of medical marijuana.

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    Re: New Research Findings in Chronic Pain

    References
    1. Eriator I, Anderson A, Tafor S, Otchere-Darko L. Community perception and response to warning signs of inappropriate drug use. Pain Med. 2007;8:106. Abstract 140.
    2. Wasan AD, Butler SF, Budman SH, Fernandez K, Jamison RN. Psychiatric history and psychological adjustment as risk factors for aberrant drug-related behavior among patients with chronic pain. Pain Med. 2007;8:112.
    3. Turk DC, Brody MC, Okifuji EA. Physicians' attitudes and practices regarding the long-term prescribing of opioids for non-cancer pain. Pain. 1994;59:201-208. Abstract
    4. Kline AT, Smith MY, Haddox D, et al. Abuser-reported sources of illegally obtained opioid medications. Program and abstracts of the American Academy of Pain Medicine 23rd Annual Meeting; February 7-10, 2007; New Orleans, Louisiana. Abstract 105.
    5. Heit HA, Gourlay DL, Covington EC. The truth about pain management: the interface of pain and addiction. Program and abstracts of the American Academy of Pain Medicine 23rd Annual Meeting; February 7-10, 2007; New Orleans, Louisiana.
    6. Covington EC, Witt W, Ray B. Opioids: good or bad? Program and abstracts of the American Academy of Pain Medicine 23rd Annual Meeting; February 7-10, 2007; New Orleans, Louisiana.
    7. Prager J. Four decades of neuromodulation. Program and abstracts of the American Academy of Pain Medicine 23rd Annual Meeting; February 7-10, 2007; New Orleans, Louisiana.
    8. Kapural L. Clinical results of spinal cord stimulation for visceral pain. Program and abstracts of the American Academy of Pain Medicine 23rd Annual Meeting; February 7-10, 2007; New Orleans, Louisiana.
    9. Kapural L, Narouze SN, Janicki TI, Mekhail N. Spinal cord stimulation is an effective treatment for intractable visceral pelvic pain. Pain Med. 2006;7:440-443. Abstract
    10. Burgess FW. Pain treatment, drug diversion, and the casualties of war. Pain Med. 2006;7:474-475. Abstract
    11. Prager JP, Mackey S, Alexander G, Schwartzman R. Breaking concepts in diagnosis and treatment of complex regional pain syndromes. Program and abstracts of the American Academy of Pain Medicine 23rd Annual Meeting; February 7-10, 2007; New Orleans, Louisiana.
    12. Tegeder I, Costigan M, Griffin RS, et al. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med. 2006;12:1269-1277. Abstract
    13. Moskowitz M, Mackie K, Huestis MA, Ratcliffe S, Mead AP, Fishman SM. Cannabinoids - a new class of analgesics. Program and abstracts of the American Academy of Pain Medicine 23rd Annual Meeting; February 7-10, 2007; New Orleans, Louisiana.


    Author Information
    Frederick W. Burgess, MD, PhD, Clinical Associate Professor of Surgery (Anesthesiology), Brown University, The Warren Alpert Medical School, Providence, Rhode Island; Attending Anesthesiologist, Rhode Island Hospital, Providence, Rhode Island

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