Bench to Bedside: Clinical Tips from APS Poster Presentations

Editor’s Memo from June 2016

By Forest Tennant, MD, DrPH

First, it is important for practitioners to know that the American Pain Society (APS) has progressively pursued research as its primary goal and mission in recent years. This point is noted here because of the outstanding research that was presented in this year’s annual meeting, held May 11-14, in Austin, Texas.

To their considerable credit, the leaders of APS want their research to be “translational”—meaning the investigatory findings are transferred from “bench to bedside” or from the laboratory to the clinic. This highlight is designed to “translate” some research information from the meeting that may have some practical application.

Sleep

Pain practitioners have long observed that pain patients who can obtain a few hours of sleep each night have less pain the next day. In a well-done study involving 139 participants with central sensitization and pain from knee osteoarthritis, fragmented sleep was associated with more pain.¹ This supports medical treatment of insomnia in chronic pain patients. (see APS Highlights).

Chronic Regional Pain Syndrome (CRPS)

This relatively rare, debilitating, and difficult-to-treat condition is being studied by many groups to hopefully improve our limited menu of options.^2,3 Although no new treatment breakthroughs were reported, a better understanding of CRPS was put forward.

First, abnormal brain structures were found among pediatric patients with CRPS who did not respond to traditional treatments (n=10) compared to CRPS treatment responders (n=19).² The structural changes included alterations in cortical thickness, subcortical volume, and dendritic atrophy. Much of our current literature implies that CRPS is a pathologic entity of the dorsal horn in the spinal cord. Now we know that the brain and spinal cord are both involved.

The dread of CRPS at the clinical level is that the condition will start in one extremity and spread to others. In a study of 150 patients, researchers found that the longer the condition existed, the more likely it was to spread to more than one extremity.³They, therefore, recommend early and aggressive therapy to hopefully prevent the condition from spreading.

Traumatic Brain Injury (TBI)

Chronic pain as a result of TBI has become increasingly common in pain practice. While it may manifest as trunk, neck, or extremity pain, constant headache is the most common result. This is no accident. A research team from the University of Maryland Department of Neural and Pain Sciences found cerebral grey matter changes in these individuals.⁴

The investigators found an “inverse relationship in the change in left S1 and thalamus grey matter volume between MRIs conducted immediately after TBI and post-traumatic headache and after 592 days, on average, with an increase in S1 and a decrease in thalamus.” Previous studies have reported decreased thalamus grey matter in TBI patients and an increased S1 in migraine patients. The current findings may be specific for patients with post-traumatic headache, noted the authors.

Therefore, don’t expect the usual and simplistic treatments for migraine and tension headaches to do the job.

Genetic Disorders

The collective research on genetics at this meeting was top notch. First, pain, usually lower back pain, was found to be present in 89% of Marfan syndrome patients.⁵ Anyone who has tried to deal with the pain flares of sickle cell disease knows it can be a frustrating experience. No wonder. This genetic disease has an extremely high percentage (over 80%) of patients who demonstrate cytochrome P450 genetic metabolic defects.^6,7 The message here is to use the opioids morphine, hydromorphone, and tapentadol (Nucynta), which are not dependent upon the cytochrome system.

Not only do sickle cell patients have cytochrome P450 defects, they also have gene polymorphism in their adrenergic receptors.⁷Some of these patients will likely require an adrenergic agent (amphetamine, methylphenidate, etc.) to control chronic pain and prevent pain flares.

Studies continue to show that certain polymorphisms of cytochrome P450 enzymes, opioid receptors, and other enzymes can identify patients who are at a higher-than-normal risk for opioid addiction and abuse.⁸ To date, there are no published studies on these addiction and abuse genetic predictors, but several are in process. It’s time for pain practitioners to start talking and thinking about the clinical and ethical activity we should undertake when we identify a patient who has a high genetic risk for addiction and abuse.

There is an accumulating body of research that links chronic pain conditions with decreased expression of the enzyme catechol-O-methyltransferase (COMT).^9-11 A genetic deficiency of COMT increases central nervous system (CNS) levels of catecholamine, helps maintain a chronic pain state, and increases opioid requirements.^10,11 Physicians are starting to test for COMT enzymes and are making clinical decisions based on COMT enzyme activity.

We urgently need a consensus effort on the real, practical meaning and actions to take with COMT testing. Forget what the labs tell us. We need facts and science. Put another way, is COMT testing friend or foe?

Opioid Resistance

It seems like everyone has a different theory as to why a patient does not respond well to opioids. Tolerance, genetics, hyperalgesia? Now there is another reason. A research team from the National Center for Complementary and Integrative Health, part of the National Institutes of Health, has found that there is decreased CNS opioid receptor availability 3 months after a peripheral nerve injury.¹²

The study, which was performed on Sprague-Dawley rats, induced neuropathic pain by causing a nerve injury to the hind paw and compared the positron emission tomography (PET) images to rats that underwent a sham surgery. Three months after surgery, injured rats were hypersensitive to both cold and mechanical stimuli compared to the control animals. They also showed reduced sucrose preference (anhedonia) compared to control animals.

The reduced opioid receptor availability was seen in the motor cortex, insula, and caudate/putamen. These findings support reports of reduced opioid receptor availability in chronic pain patients and show that such effects may be caused by the chronic pain condition rather than being a predisposing factor.

In my opinion, this finding is profound and may help explain the ceiling effect of opioids. It may provide another reason why some patients do not respond to lower doses of opioids.

Neurosteroids

Dehydroepiandrostenedione (DHEA) and DHEAS (sulfated form) are neurosteroids that modulate gamma-aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptors in the CNS. Female veterans who served in the conflicts in Afghanistan or Iraq and who had high pain levels were found to have low levels of DHEA and DHEAS.¹³ Practical Pain Management has long advocated the testing of relevant hormones and their temporary replacement when found deficient. This is one more study to support hormone profile testing and treatment.

Low-Dose Naltrexone

Low-dose naltrexone has become a common treatment for chronic pain patients who haven’t yet been started on opioids. Although naltrexone is primarily used in fibromyalgia, a dose of 2 to 4.5 mg a day was found to be effective in other chronic pain conditions.¹⁴ Its mechanism appears to be attenuation of the proinflammatory response initiated by microglia cell activation.

Oral Ketamine

It has been known for some time that ketamine infusion can reduce pain and the need for opioids, at least for a short time period.³ In a randomized, placebo-controlled trial of 32 subjects, researchers found that an effective oral dose of ketamine can reduce pain and opioid use.¹⁵ The average oral daily dosage was 101 mg, with a wide range of 16 to 256 mg.

Opioid Sparing With Baclofen

Every practitioner wants to lower a patient’s opioid dosage, particularly those legacy patients who were prescribed high dosages several years ago and remain on high opioid dosages. There is overlapping expression of GABA and opioid receptors in the CNS. In a controlled study in rats, the concurrent administration of baclofen and the opioids morphine, oxycodone, buprenorphine, and fentanyl increased analgesia and reduced the need for opioids.¹⁶ Practitioners can give this simple measure a try to reduce opioids.

Metformin

Originally marketed as an agent for Type 2 diabetes, metformin has found a number of novel uses in clinical practice. Now some innovative researchers have discovered that metformin decreases the activation of glial cells in the spinal cord.¹⁷ The researchers reported complete resolution of pain in some rats that had induced neuropathic pain. This drug needs our immediate attention.

Scramble Therapy

No, this isn’t about eggs for breakfast. It refers to the simultaneous use of 16 electrical currents that produce normal nerve action potentials.¹⁸ The theory is that abnormal pain signals can be replaced with “non-pain” signals. The researchers report some good results in a variety of neuropathic pain states.Practical Pain Management has long encouraged practitioners to bring electric current and/or electromagnetic therapies into their practice. The “scramble” approach is a most innovative one, and it needs clinical experience and feedback.

The above is an attempt to bring some nuggets of research information to the practicalities of clinical practice. My hope is to foster respect and communication between front line practitioners and basic science researchers. Frankly, that respect and communication has for whatever reason, somewhat disappeared in recent years to the detriment of our cause. This memo is my first shot to encourage “bench to bedside.” Let me know where we go from here.

References

Burton E, Campbell C, Robinson M, et al. Sleep mediates the relationship between central sensitization and clinical pain. Poster presented at:
Annual Meeting of the American Pain Society; May 11-14, 2016; Austin, TX. Poster 322.
Kim P, Hinkle C, Zhand R, et al. Regional brain structure differences in learning, motivation, and emotion between treatment responders and non-responders in pediatric CRPS. Poster presented at: Annual Meeting of the American Pain Society; May 11-14, 2016; Austin, TX. Poster 219.
Rudd-Barnard G, Wallborn A, Pangarkar S, et al. A case study investigating opioid medication utilization in patients with complex regional pain syndrome before and after ketamine infusion therapy. Poster presented at: Annual Meeting of the American Pain Society; May 11-14, 2016; Austin, TX. Poster 406.
Burrowes S, Sours C, Meeker J, et al. Cerebral grey matter changes associated with post-traumatic headache in mild traumatic brain injury patients: a longitudinal MRI study. Poster presented at: Annual Meeting of the American Pain Society; May 11-14, 2016; Austin, TX. Poster 339.
Speed T, Mathur V, Christensen B, et al. Characterization of pain, disability, and psychological burden in Marfan Syndrome. Poster presented at: Annual Meeting of the American Pain Society; May 11-14, 2016; Austin, TX. Poster252.
Jaja C, Lyon M, Patel N, et al. Genetic variability of UGT287, CYP3A4, CYP3A5 and CYP2B6 DMETs in a sickle cell disease patient cohort. Poster presented at: Annual Meeting of the American Pain Society; May 11-14, 2016; Austin, TX. Poster 281.
Jhun E, He Y, Yao Y, et al. Beta2-adrenergic receptor gene polymorphisms and haplotypes associated with chronic pain in sickle cell disease. Poster presented at: Annual Meeting of the American Pain Society; May 11-14, 2016; Austin, TX. Poster 283.
Blanchard J, Anand N, Meshkin S, et al. Opioids and genetics: RS2740574 in CYP3A4 may impact the risk of opioid abuse, misuse, and/or addiction. Poster presented at: Annual Meeting of the American Pain Society; May 11-14, 2016; Austin, TX. Poster 200.
Ciszek B, O’Buckley S, Nackley A. Peripherally located beta2- and beta3-adrenergic receptors contribute to the development of COMT-dependent pain in rats, but not the maintenance of pain in COMT-/- mice. Poster presented at: Annual Meeting of the American Pain Society; May 11-14, 2016; Austin, TX. Poster 312.
Hartung J, Ciszek B, O’Buckley S, et al. Distinct mechanisms underlie the development and maintenance of COMT-dependent pain. Poster presented at: Annual Meeting of the American Pain Society; May 11-14, 2016; Austin, TX. Poster 374.
Anand N, Kantorovich S, Meshkin B, el al. Assessing pain perception by genetic testing of COMT haplotypes influences clinical decisions for chronic non-cancer pain patients. Poster presented at: Annual Meeting of the American Pain Society; May 11-14, 2016; Austin, TX. Poster 476.
Thompson S, Pitcher M, Tarum F, et al. Decreased opioid receptor availability in rat brain three months after peripheral nerve injury. Poster presented at: Annual Meeting of the American Pain Society; May 11-14, 2016; Austin, TX. Poster 335.
Naylor J, Kilts J, Strauss J, et al. Neurosteroid levels are inversely associated with low back pain in female Iraq/Afghanistan veterans. Poster presented at: Annual Meeting of the American Pain Society; May 11-14, 2016; Austin, TX. Poster 419.
Noon K, Sturgeon J, Kao M, et al. A novel glial cell inhibitor, low-dose
naltrexone, reduces pain and depression, and improves function in chronic pain: a CHOIR study. Poster presented at: Annual Meeting of the American Pain Society; May 11-14, 2016; Austin, TX. Poster 418.
Grande L, Delacruz H, Thompson M, et al. Oral ketamine for chronic pain: a 32-subject placebo-controlled trial in patients on chronic opioids. Poster presented at: Annual Meeting of the American Pain Society; May 11-14, 2016; Austin, TX. Poster 417.
Sorge R, Totsch S, Landis A, et al. Baclofen and opioid synergism in mice. Poster presented at: Annual Meeting of the American Pain Society; May 11-14, 2016; Austin, TX. Poster 360.
Inyang K, Szabo-Pardi T, Price T. Treatment of chronic pain: long-term effects of metformin on chronic neuropathic pain and microglial activation. Poster presented at: Annual Meeting of the American Pain Society; May 11-14, 2016; Austin, TX. Poster 309.
Lesenskyj A, Maxwell C, Cruciani R. Neuropathic pain reduction with scrambler therapy treatment. Poster presented at: Annual Meeting of the American Pain Society; May 11-14, 2016; Austin, TX. Poster 393.