I describe my struggle with prescribing opiates for people in chronic pain. My observation has been that my patients on opiates don't seem to be in any less pain than my patients not on opiates, and sometimes they are more grumpy. I explore the literature and learn that prolonged opiate use sensitizes people to feel more pain and that it can also act as a neurotoxin producing neuropathic-like pain, so perhaps not a good idea

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Recently I have been amazed at the number of people receiving opiates chronically for pain.   I have been challenged in my practice about how to respond to these people and whether or not to prescribe opiates or start people on opiates when they ask.   Some of the people I meet have been on opiates for years at relatively high doses, so I wondered about the risks of benefits of these practices.   I am reticent to start opiates among people who are not taking them, but likewise, I don't want to suddenly stop opiates for those people who have been taking them for years.

I found a paper written by Drs. Jane Ballantyne and Jianren Mao called Opioid therapy for chronic pain and published in The New England Journal of Medicine (Volume 349, no. 20, pages 1943-53, 2003).   These authors wrote that the published trials on opiate use for chronic pain left two important questions unanswered: Is opioid therapy beneficial in the long term (over a period of years rather than months), and does the dose have an effect on the efficacy and the safety of long-term therapy? Few, if any studies, have addressed these questions.   A fundamental principle of acute pain management is that the dose of an opiate should be increased until maximal analgesia is achieved with minimal side effects. Experts advise that in the treatment of chronic pain the initial dose increases should be achieved within weeks, doses should be moderate and further increases in the dose should be introduced with extreme caution.¹   However, my experience has been that many physicians take a much more liberal approach to dose increases. Some patients with chronic pain receive doses as high as 1 g or more of morphine (or a morphine equivalent) per day, which may be five or more times the doses validated by the literature (see Ballantyne and Mao).   In my experience and in that of Drs. Ballantyne and Mao, patients receiving opioid doses of this magnitude rarely report satisfactory analgesia or improved function.   Although the clinical trials carried out to date have not examined the efficacy and safety of prolonged, high-dose opioid therapy, they say that evidence is rapidly accumulating that, in the treatment of patients with chronic pain, opiate doses should be limited in order to maintain both efficacy and safety.

I find these patients who are on high dose opiate therapy and still complaining of severe pain difficult to manage.   Clearly, the answer is not to further increase their already high dose of opiates, get this is what they demand and feel entitled to receive.   Since tolerance develops, the doses requested become higher and higher and for uncertain benefit.

So what is chronic pain?   The International Association for the Study of Pain states that it is pain that persists past the healing phase following an injury.²     However, it's difficult to know when the healing phase ends, so most people definite chronic pain as pain persisting 6 months after the initial onset.   We know from animal studies that the nerves in the spinal cord that transmit pain signals to the brain undergo dramatic reorganization during those six months in which the pain becomes chronic.^{3, 4}   The brain also remodels itself over time to feel more pain than it is currently feeling.   The process in both the spinal cord and the brain has been called allodynia.   Most of us have experienced during the course of recovery from a sunburn in which even a gentle breeze against the burn feels painful.   Once this remodeling has happened, then reducing chronic pain requires changing the brain.   Within the brain, large overlaps exist between the circuits that manage pain from the body and social pain, sadness, and emotional distress, and it is difficult, if not impossible, to tease apart the pain related to signals from the body, to sadness, and from our sense of distress.

Further complicating matters is the belief of many patients that the cause of their pain can be located by an X-ray.   Patients often bring me their X-rays to "prove" that their pain is "real".   Actually, they don't have to prove pain to me.   I understand that pain is real, though I believe the perception of pain occurs in the brain itself (just as does our perception of all body sensation, including vision, hearing, smell, and touch).   Studies don't actually prove that X-ray findings have any relation at all to pain.   Dr. Maurits van Tulder and colleagues reviewed all the available studies on this matter to determine if there was a relationship between X-ray findings and back pain.   They concluded that no firm evidence existed for the presence or absence of a causal relationship between X-rayfindings and back pain.

So what about this phenomenon of tolerance that I introduced above? Opioid tolerance develops with the repeated use of opioids and brings about the need to increase the dose to maintain pain relief.   There are two types of tolerance, association or learned and non-associative or adaptive.   Associative tolerance is linked to environmental cues and involves psychological factors, mediated in part through the seeking system of our brains so well-described by Jaak Panksepp.   The seeking system is also called the mesocortical dopamine system and it drives us to seek for things.   Seeking has been found in studies to be more rewarding than findings.   Patients on opiates learn to seek opiates.   Nonassociative tolerance is an adaptive process at the cellular

level that involves a reduction in the turnover rate and number of receptors to opiates and/or a reduction in the sensitivity of these receptors to opiates.^6-8   In patients receiving prolonged opioid therapy, increased production of an opiate made by the body itself (called dynorphin) has been found in the spinal cord dorsal horn neurons (where the relay station happens between the nerve coming to the spinal cord from the body and the nerve going into the spinal cord).    This is associated with enhanced sensitivity to pain and may be an important reason why opiates do not seem to provide long-term pain relief.

Long-term use of opioids also appears to be associated with the development of abnormal sensitivity to pain. Studies suggest that this opiate-induced abnormal pain sensitivity has much in common with the neuropathic pain^10,11 and has been observed in patients treated for both pain and addiction.^12-15 Animal studies suggest that the cause is irreversible neurotoxic changes including cell death mediated through the NMDA-receptor.^16-18

I continue to prescribe opiates for people who are already taking them if they are willing to work with me to address some of the other aspects of their chronic pain and to learn methods of managing pain that are not opiate-driven.   This is primarily because of my own experience that increasing the opiate dose doesn't actually seem to improve function or reduce pain on a long term basis.   It seems to have a temporary effect which wears off by the end of the month when further dose increases are requested.   What I require is that people

1.   Attend our pain management/education group at least twice monthly.   We complete pain diaries during the group along with measures of the severity and type of pain.

2.   Engage in body/movement therapy of some type at least once weekly.   This can be physical therapy, yoga, t'ai chi, chi gong, or supervised exercise.

3.   Be willing to try non-opiate medications which can reduce reliance on opiates.

4.   Undertake counseling with someone knowledgeable of pain for at least two sessions per month, either within our practice or outside of it.

Patients are often skeptical about being asked to move, but studies confirm that this is helpful for back pain.   For example, Dr. Claus Manniche and colleagues at the University of Copenhagen⁹ studied the effect of 30 sessions of intensive dynamic back extensor exercises for patients with chronic low back pain over 3-months.   They divided their 105 patients into 3 groups: a treatment group, an alternative group which underwent 20% of the treatment group's exercise program, and an alternative group in which treatment consisted of heat, massage and mild exercise. The exercises worked as long as one year afterwards. Irrespective of sex, age, duration and degree of severity of back trouble, or of pre-existing sciatica or abnormal findings upon X-ray of the spine, patients obtained a favorable result from the training program.   No one got worse as a result of the program.

I am willing to increase opiate medication if pain increases, but only when that increase can be justified by a documentable improvement in function on some important level (work, activities of daily living, ability to care for others, etc.).   Otherwise I can only increase opiate doses with the support of a consultation from an established pain clinic physician who agrees that an increase in opiates is warranted.   I have found that rarely does the pain clinic at Dartmouth University, which is the one closest to me, recommend opiate therapy in a patient who is not taking these drugs, when the condition is not life-threatening and shows no definite likelihood of quick resolution.   Nevertheless, I like patients to hear this for themselves.   I use Dartmouth to prevent me from seeming like the bad guy who's standing in their way of relief.   This is because the road to relief is not an opiate freeway but a rather bumpy, narrow country road with deep ruts and pot holes.   Like Old County Road near my friends in Stamford, Vermont, it may have been abandoned by the County 20 years ago and will only cause your axle to break should you try to drive on it.

Lost prescriptions are not refilled, so I recommend keeping opiates under lock and only carrying a small amount on one's person.   If this is a problem, we can prescribe lower quantities -- either one week at a time or two weeks at a time.   Keep these pills away from dogs, toilets, sinks, and microwave ovens.  

For all these reasons, I believe we need to work together to create communities of pain sufferers, to change their brains through social interaction (the social brain hypothesis) and to help each other to live better lives with or without pain.   I'm all for anything that works, but not for harm or for approaches in which the risks may outweigh the benefits.

1. Urban BJ, France RD, Steinberger EK, Scott DL, Maltbie AA. Long-term use of narcotic/antidepressant medication in the management of phantom limb pain. Pain 1986; 24:191-6.

2. Merskey, H., Bogduk, N., 1994. Classification of Chronic Pain. IASP Press, Seattle, WA.

3. Woolf, C.J., Salter, M.W., 2000. Neuronal plasticity: increasing the gain in pain.

Science 288, 1765--1769.

4.   Woolf, C.J., Salter, M.W., 2006. Plasticity and pain role of the dorsal horn. In:

McMahon, S.B., Koltzenburg, M. (Eds.), Textbook of Pain. Churchill-Livingstone,

New York, pp. 91--105.

5.   van Tulder, Maurits W. PhD; Assendelft, Willem J. J. MD, PhD; Koes, Bart W. PhD; Bouter, Lex M. PhD. Spinal Radiographic Findings and Nonspecific Low Back Pain: A Systematic Review of Observational Studies Spine: 15 February 1997 - Volume 22 - Issue 4 - pp 427-434.

6. Alvarez V, Arrtamangkul S, Williams JT. A RAVE about opioid withdrawal. Neuron 2001;32:761-3.

7. Finn AK, Whistler JL. Endocytosis of the mu opioid receptor reduces tolerance and a cellular

hallmark of opiate withdrawal. Neuron 2001;32:829-39.

8. South SM, Smith MT. Analgesic tolerance to opioids. Pain Clinical Updates. December 2001:1-4.

9.   Manniche, C., Lundberg, E., Christensen, I., Bentzen, L., & Hesselsøe, G. Intensive dynamic back exercises for chronic low back pain: a clinical trial. Pain, Volume 47, Issue 1, October 1991,

10.   Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and opiate tolerance: a current view of their possible interactions. Pain 1995;62:259-74.

11.   Mao J, Price DD, Mayer DJ. Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C. J Neurosci 1994;14:2301-12.

12.   Brodner RA, Taub A. Chronic pain exacerbated by long-term narcotic use in patients with

non-malignant disease: clinical syndrome and treatment. Mt Sinai J Med 1978;45:233-7.

13. Taylor CB, Zlutnick SI, Corley MJ, Flora J. The effects of detoxification, relaxation, and brief

supportive therapy on chronic pain. Pain 1980;8:319-29.

14. Savage SR. Long-term opioid therapy: assessment of consequences and risks. J Pain Symptom Manage 1996;11:274-86.

15. Compton MA. Cold-pressor pain tolerance in opiate and cocaine abusers: correlates of drug type and use status. J Pain Symptom Manage 1994;9:462-73.

16. Mao J, Sung B, Ji RR, Lim G. Neuronal apoptosis associated with morphine tolerance: evidence for an opioid-induced neurotoxic mechanism. J Neurosci 2002;22:7650-61.

17. Chaney MA. Side effects of intrathecal and epidural opioids. Can J Anaesth 1995; 42:891-903.

18. Giffard RG, Morgan RL. Cell death in the central nervous system: therapeutic possibilities? Reg Anesth Pain Med 2000;25: 22-5.

Authors Website: www.mehl-madrona.com

Authors Bio:
Lewis Mehl-Madrona graduated from Stanford University School of Medicine and completed residencies in family medicine and in psychiatry at the University of Vermont. He is the author of Coyote Medicine, Coyote Healing, Coyote Wisdom, and Narrative Medicine.