Pain is a highly individual experience, and therefore demands a personalized approach for its management. For each patient, various psychosocial, biomedical, and environmental factors converge to produce pain that is unique to that individual. This understanding of how pain is experienced and how it should be treated was an underlying theme of several lectures presented at the 15th Symposium on Functional Medicine last May. In addition to the latest research findings, the conference provided practical and thought-provoking discussions from expert clinicians and scientists. Here are a few highlights from four of those presentations.

The Genetic Connection to Pain: Nurture and Nature—
Jeffrey S. Mogil, PhD

Like many other complex biological phenomena, pain is now being studied at the level of the gene. Pain is a subjective experience that displays considerable variability compared to other sensory modalities. In some instances and in some people, intensely noxious stimuli are not perceived as causing pain, whereas other people can experience excruciating pain from light touching of the skin. Some patients are highly sensitive to pain relief from placebo administration, while others are insensitive to even high doses of morphine.

Dr. Mogil, of the Centre for Research on Pain at McGill University, Montreal, reviewed the evidence for the hypothesis that variations in pain and analgesic responsiveness can be attributed in part to genetic differences. He and his colleagues have found that:

• The genes that determine who gets osteoarthritis and the genes that determine how much the osteoarthritis hurts are different.
• 70% to 80% of redheads have completely nonfunctioning melanocortin 1 receptors, making them 25% less sensitive to pain than blondes.
• Individual experience of pain is determined by both the experience of the patient and the experience of people in the patient’s environment.
• Pain can weaken one’s immune system and increase susceptibility to infections or cancer.

Pain as a Metaphor for Dysfunction—
Jeffrey Bland, PhD

“A pain in the neck.” “A pained expression.” “It was a painful reminder.” The English language is filled with expressions using pain as a metaphor for dysfunction. Yet one cannot judge a person’s subjective experience of pain from any traditional physiological or pathological marker, according to Dr. Bland, founder of the Institute for Functional Medicine. The intensity, frequency, and duration of pain are highly individualized and relate to many variables, including the context of the painful situation coupled with the individual’s physiological and psychological state before the event that triggered the pain.

“Pain is not a disease, it is a message,” said Dr. Bland, calling for a fundamental change in the way doctors manage pain. Among Dr. Bland’s main points:

• Pain occurs as a result of “a distortion in the neuroendocrine-immune web.” In order to assess and treat pain, one must examine this system as a whole; describing it in parts is like examining an elephant with a microscope. “You cannot describe a systems biology experience, which pain most certainly is, by looking at and describing its constituent parts.”
• There’s a reason fish oils seem to be so good for so many different conditions, including chronic pain problems. It is because omega-3 fatty acids work at a “metabolic acupuncture point.” They’re hormetic, meaning they have an unexpectedly large effect based on a relatively small amount given. This is because they affect multiple aspects of the neuroendocrine web all at once.
• Probiotic cell wall materials bind to endocannabinoid receptors, which induce a systemic analgesic response. Therefore, in irritable bowel syndrome (IBS), for example, probiotics can reduce gut and systemic pain.

How We Filter Pain: Adaptation to Environmental Stimuli—
Sonia Lupien, PhD

Pain is a complex, adaptive response involving several areas of the brain transmitting information back and forth. When there is an absolute threat to survival, it leads to tunnel vision for the brain which must direct all attention on what the organism needs to survive. Thus, threats of pain can lead to an attentional bias toward painful stimuli. Dr. Lupien, founder of the Centre for Studies on Human Stress, Douglas Hospital, Montreal, discussed the idea of attentional bias toward pain-related stimuli, how this develops, and how we can begin to modulate this phenomenon. She pointed out that:

• The level of attention we give to an event depends on its emotional valence. A stressful situation emotionally charged and hard to ignore. Thus, threat processing produces an internal interference on usual cognitive processes and can lead to an attentional bias toward painful stimuli. This attentional bias can produce painful memories and hypervigilance, as in posttraumatic disorder.
• In IBS, the brain may become extremely sensitive to information about pain, which may be less relevant for someone else who would therefore not pay attention to it. Thus, the initial pain creates an attentional bias leading to more pain perception. In other words, pain begets pain.
• Our early experiences shape our attentional processes and biases, determining which stimuli we respond to. This is evidenced by the fact that many chronic pain patients experienced childhood abuse. Research on abused children has shown that they are very sensitive to information that signals a potential threat and have more fear in response to these signals.
• After trauma, information about the traumatic situation is inhibited for 14 days, so victims of abuse or other violence may have trouble recalling the facts of what happened during this 2-week period. Dr. Lupien thinks that in asking the victim to recall what happened, we are reactivating a memory that wants to sleep, and this can have long-term implications.
• Virtual reality systems have been used to modify attentional bias and push patients to pay attention to stimuli other than pain-related stimuli. For example, a burn patient may benefit from a virtual reality experience of a cold environment. In addition, listening to music you like can produce music-induced analgesia and reduce stress reactions.

Using Pharmacogenomics in Pain Management: Ready for Prime Time?—
Patrick Hanaway, MD

Pharmacogenomics is the study of the interaction between genes and pharmaceuticals, herbs, or nutraceuticals. Recently there has been an explosion in knowledge relating to the genetics of drug metabolism. Inter-individual variability in response to drug therapy is the rule, not the exception, for almost all medications. But how much can we use pharmacogenomics to tailor our pain control therapies and to decrease between-patient variability?

In his talk, Dr. Hanaway, Chief Medical Officer of Genova Diagonstics, Asheville, NC, reviewed the metabolic variability found in Phase I and Phase II hepatic detoxification systems in order to highlight the importance of drug-drug interactions, as well as to evaluate the effect of genetic polymorphisms (i.e., single nucleotide polymorphisms or SNPs) on the metabolism of pain medications. Clinical pearls from his talk included the following:

• Many drugs rely on phase I detoxification for activation. For example, codeine + hydroxyl group = morphine. If a patient can’t convert codeine to morphine well (i.e., he or she is a “poor metabolizer”), codeine would be a poor analgesic choice. On the other hand, a patient who converts it very quickly (i.e., an ultra-metabolizer) will experience spikes in codeine’s analgesic effect.
• The cytochrome P450 pathway 2C9 is involved in metabolism of NSAIDs, tramadol, TCAs, sildenafil, sulfa drugs, phenobarbital, marijuana, losartan, and warfarin. People who have the two principal SNPs of CYP2C9 metabolize these drugs more slowly, and are at increased risk of adverse effects from these drugs.
• SSRIs, silymarin, and azole antifungals are inhibitors of 2C9 and slow down that metabolic pathway even further, which could compound risk in patients on multiple drugs.
• Cytochrome P450 pathway 2C19 is responsible for metabolism of antiepileptics, PPIs, estrogen drugs, propranolol, prednisone, and warfarin. People with a SNP for this pathway cannot metabolize these drugs well; they usually need lower doses to ensure safety.
• People who do not have proper 2C9 and/or 2D6 activity have a reduced ability to inactivate COX-2 inhibitors. They will likely have increased circulating levels of COX-2 inhibitors and therefore increased risk of kidney damage and cardiovascular disease.
• The UGT enzyme is involved in helping opioids bind to their receptor. If UGT activity is decreased, morphine does not bind effectively, decreasing the response to pain medication.
• People with the COMT SNP have increased pain sensitivity and increased risk of chronic pain and fibromyalgia. Practitioners can help them by making sure they have enough B vitamin analogs so that they have enough methyl groups to fuel detox pathways. Supplementing with SAMe and antioxidants and limiting alcohol is also beneficial.

The IFM’s 16th International Symposium titled, “Illuminating the Path Forward: Integrating New Approaches for the Evaluation and Treatment of Mood Disorders” will be held on May 27–30, 2009, at the Westin Diplomat Resort & Spa, Hollywood, FL. For more information, visit: www.functionalmedicine.org.