Does the Location of Pain Matter?

Editor’s note: The second North American Pain School (NAPS) took place June 25-29, 2017, in Montebello, Quebec, Canada. An educational initiative of the International Association for the Study of Pain (IASP) and Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), and presented by the Quebec Pain Research Network (QPRN), NAPS brings together leading experts in pain research and management to provide 30 trainees with scientific education, professional development, and networking experiences. This year’s theme was “Where Does It Hurt and Why: Peripheral and Central Contributions to Pain Throughout the Body.” Six of the trainees were also selected to serve as PRF-NAPS Correspondents, who provided firsthand reporting from the event, including interviews with NAPS’ six visiting faculty members and summaries of scientific sessions, along with coverage on social media. Below is a summary of a graduate student debate that took place at NAPS.

Does the Location of Pain Matter?

NAPS trainees present their arguments at graduate student debate

After five days of intense learning, a sugar shack dinner—a unique Québécois
tradition—downward-facing dogs in morning yoga sessions and only a hint of capsaicin in a workshop on human experimental pain testing, it was time for the NAPS trainees to step up to the plate: to use all ammunition in their cognitive arsenal to battle it out for the prestigious accolade of winning the graduate student NAPS debate.

With only one gin and tonic on board for Dutch courage, the graduate students took on the resolution: “The biological mechanisms of and optimal treatment for pain depend on the location of that pain.”

The debate was moderated by NAPS Director Jeffrey Mogil, McGill University, Montreal, Canada, who took an initial closed count of those for or against the resolution. He assured audience members that he was at least as reliable as PricewaterhouseCoopers accountants in doing the tallying, and that it was the swing in opinion that mattered.

The “pro” team

Megan Miller, Indiana University-Purdue University, Indianapolis, US,
kicked off for the pro side by drawing inspiration from that afternoon’s white water rafting experience, asking of her audience if anyone was suffering from muscle soreness. If so, would they like some cognitive behavioral therapy or pregabalin to alleviate their pain? No! Surely what those intrepid rafters would really want is a therapy, such as a topical cream or cooling treatment, targeted to the location that hurt—the muscles. Would they put that cream in their eye? Certainly not, since location is critical to the underlying mechanisms and treatment of pain.

Using evidence presented by NAPS executive committee member Anne-Louise Oaklander, Harvard Medical School and Massachusetts General Hospital, Boston, US, during a workshop on interviewing and diagnosing pain patients, Miller further argued that a physician taking a history about pain would be negligent not to include questions about pain location.

Further bolstering her case, Miller said that treatments like lidocaine patches would never be applied to the face to treat pain in the leg. She did, however, acknowledge that some treatments work equally well at different locations, especially if there are similar underlying pain mechanisms involved. Those mechanisms are not exclusive to a location, but they do depend on location, she added.

Ashley Reynolds, Medical College of Wisconsin, Milwaukee, US, then took over for the pro team, contending that in cancer pain, there are many underlying pain mechanisms that are location dependent. For example, in metastatic bone cancer pain, cytokines released by damaged bone cells produce inflammation that leads to pain, but if those same metastatic cells spread to a different location, such as the liver or lung, pain is less of an issue. Therefore, location is crucial to symptoms of pain.

Reynolds also argued that the use of systemic, non-targeted treatments such as opioids can cause detrimental side effects including opioid-induced hyperalgesia. Disregarding the location of pain can therefore have deleterious consequences when it comes to deciding on optimal therapy.

With that she bowed to the experience of her elders, asserting that if she had not convinced the audience members, then they should listen to the experts. And so appeared a video of Mogil himself clearly stating—although in a voice unrecognizable as his own—that “location is important to pain.” (It must be acknowledged that the recorded voice sounded eerily like that belonging to pro team debater Rob Ungard, McMaster University, Hamilton, Canada. However, whether Mogil’s voice had indeed been dubbed has neither been confirmed nor denied at the time this article went to press).

The “con” side

Next up was the “we the cons” team, beginning with Rebecca Brouillette, Université de Sherbrooke, Canada, and Sarah Najjar, University of Pittsburgh, US, who put their argument forward in a perfectly-timed double act. Using a splendid color scheme for their slides, they pointed to the inherent difference between nociception and pain. Nociception is the neural process for encoding noxious stimuli whereas pain is an unpleasant sensory and emotional experience. In order to experience something, a human must be conscious, thus pain must be in the brain, no matter where the noxious stimulus comes from in the body.

They further stressed that pain location can actually be misleading. For example, during myocardial infarction, the problem is in the heart but often pain is felt in the arm. Here physicians would be negligent if they treated the pain in the arm without realizing that the location of pain was not the most important problem. Brouillette and Najjar also pointed to phantom limb pain as a case where an amputee experiences pain even though the location no longer exists! Therefore, pain location cannot be the be-all and end-all.

The cons then turned to optimal treatments for pain. First, drugs are usually administered orally, intravenously or subcutaneously completely independent of pain location, whether acting centrally or peripherally. Physical treatments like yoga are also employed for a multitude of locations that are painful. Finally, psychological interventions such as hypnosis, distraction, and cognitive behavioral therapy succeed independent of pain location.

No matter where pain originates, they concluded, pain is in the brain and most therapies do not depend on location. In true acronym (and Canadian!) style they finished with the assertion that the pro team’s argument was LAME: Locations Aren’t Mechanisms, Eh?!?

The rebuttals

The con team was quick with a challenge from Andrew Kim, Krembil Research Institute, Toronto, Canada. He stressed that although much had been said about biological mechanisms, the pro team (arguing that location matters) had not actually defined what a mechanism is and asserted that location is irrelevant when trying to elucidate one.

He went on to say that when physicians ask patients about the location of pain to find a mechanism, they don’t care about the location itself. Several conditions, although seemingly localized such as trigeminal neuralgia, migraine and arthritis, have some shared mechanisms independent of the location. If the same pain signal reaches the brain from different locations, the pain experience is the same regardless of where the input came from.

Finally, Kim said that the use of topical therapy for muscle pain following rafting was not location-specific but “type”-specific; of course the mechanism of muscle pain should be treated but this does not require a strictly location-based approach.

Next up, Rob Ungard took on the rebuttal against the con team (which had been arguing that location was not important). He acknowledged that the cons had argued a difficult stance well and performed an interesting intellectual exercise. But their statements, he said, did not reflect the clinical reality that diagnosis relies on pain location. Further, he agreed that peripheral pain conditions can alter the central nervous system, but the pattern of central changes that arise still depends on the location of the original injury.

He also refuted the con team assertion that physical and psychosocial-based pain therapies cannot be location-specific just because these treatments are used in many pain conditions affecting different locations. Knowing the mechanism without the location will never lead to optimal treatment. For example, if a patient breaks a bone, the doctor wants to know which bone is broken in order to treat it properly.

The con team consistently argued that “pain is in the brain,” but Ungard had an answer for that too: you might want to treat pain in the brain for someone with a broken bone, but again, you also want to pay attention to which specific bone was broken in order to restore function and treat pain optimally. And he turned the example of phantom limb pain on its head, stressing that location in that condition is critical for interventions such as mirror box therapy, which is in fact location dependent.

Ungard finished by evoking the wise words of NAPS visiting faculty member Martin Schmelz: while a person has a brain that processes pain, the particular nociceptive input determines the brain response. The phone lines don’t tell you about the conversation; for the full picture you need to know who is talking on both ends, and location fills in that gap. With a flourish, he again quoted Schmelz, stating of his pro team, “this is living” and of the con team, “that is dreaming.”

Closing arguments

The pro team (location matters) closed by reiterating that medications for different conditions depend on the underlying mechanism, which, in turn, depends on location. Calia Torres, University of Alabama, Tuscaloosa, US, resplendent in a pair of sunglasses at an evening event, pointed to the example of endometriosis. She tossed aside the idea that when investigating pain from this condition a doctor would ignore the location, the endometrium itself.

Torres revealed why she was wearing sunglasses at night, claiming she had an eye infection resulting in photophobia and eye pain. Treatment for this ailment would include sunglasses and topical antibiotics—both of which are location specific.

Sarah Rosen, McGill University, then summed up for the con team. While acknowledging the importance of location, she said it is not sufficient to explain mechanisms nor to direct treatments. She reiterated this contention in a very elegant way by pointing to referred pain as an example of how location can mislead when trying to understand pain mechanisms. As for phantom limb pain, she reminded the audience that mirror therapy is a method of training the brain, rather than a treatment directed at a location. She also noted that the somatotopic map for pain is not nearly as localized as the map for touch.

Finally, Rosen repeated the argument that so many therapies target the mechanisms that drive pain but in a way that is independent of location; treatment aiming to reduce pain catastrophizing is a good example. Even physiotherapy gets people to move in general, rather than focus on a specific location. Finally, many drugs are rarely targeted to a specific site, but towards mechanisms instead. While location may indicate certain elements of pain, it is not sufficient to treat it.
And so ended the debate, a well-fought battle by all, thoroughly enjoyed by the baying masses.

The 2017 North American Pain School voted again: it was a very tight contest resulting in a (slender) win for the con team, having swung three votes to their side from the original count.