Gila, genomica, and more: emerging trends in pain management (Proceedings)

Rapid advances are being made in understanding the neurobiology of pain, which in turn reveal potential new targets for prevention and treatment.

Gender and Age

The role of gender in pain is already clearly evident in humans, with women generally more prone to higher pain scores. In both human and in animal models, gender-based differences in opioid sensitivity suggest that analgesic protocols should be predicated in part on whether the patient is male or female. The implications for dogs and cats may be compounded given the widespread practice of sexually altering dogs and cats (for example, does castration put male dogs at higher risk for chronic pain states?).

Age plays a vast role in pain and central nervous system plasticity Furthermore, there are significant age-related differences in drug pharmacokinetics, due to changing metabolic status, body composition, protein-binding characteristics, and so on. How these differences are expressed will become more evident in the years to come and are likely to be a primary determinate of patient-specific pain management strategies.

Research efforts are underway for pharmacologic interventions of specific receptors and neurotransmitters in the pain-modulating pathway. Currently popular medications may in the future be available in novel combinations which will help to widen their safety margins considerably and thus expand their utility.

New in NSAID's (Europe only)

     • robenacoxib (Onsior®): chronic pain in dogs and acute pain in cats.

     • mavacoxib (Trocoxcil®) - sustained-release NSAID approved for chronic pain in dogs. A 2010 search for literature yielded an abstract on the pharmacokinetics of the drug2 but no information on efficacy; the manufacturer reports 30 days after 1 dose.

     • nitronaproxen (Naproxcinod®,) is a cyclooxygenase-inhibiting nitric oxide-donating drug (CINOD) in Phase Iii trials that appears to have the analgesic efficacy of the parent NSAID but with a greatly reduced incidence of negative side effects because of the positive effects of the NO.8 Naproxcinod has been shown to control the pain of osteoarthritis.

New in Opioids

     • Extended-release formulations or delivery devices

     • methadone

     • Peripheral mu-R antagonists: alvimopan PO (Entereg®), for post-operative ileus, methylnatrexone SC (Relistor®) for constipation

Other New Drugs

     • duloxetine (Cymbalta®) – SNRI

     • milnacipran (®)- SNRI

     • cyclobenzaprine (Flexeril, Fexmid, Amrix ®)- muscle relaxant with a chemical structure similar to tricyclic antidepressants

     • tapentadol (Nucynta™) - centrally acting analgesic with a dual mode of action similar to that of tramadol

     • pregabelin (Lyrica® ) – structurally similar to gabapentin but with superior kinetic profile

     • topiramate (Topamax®)- anticonvulsant drug with efficacy against migraine headaches

     • tizanadine (Zanaflex®, Sirdalud ®)- oral centrally-acting alpha-2 agonist

     • ziconotide (Prialt ®)- N-type voltage-gated calcium channel blocker for intrathecal use

     • capsaicin (Adlea™, Resiniferatoxin (RTX) – acts on transient potential vanilloid 1 receptor (TRPV1) receptor

     • Glial inhibitors: Glial cells (astrocytes, microglia, oligodendrocytes) in the spinal cord, whose purpose was once thought to be merely structural and macrophage-like in nature (providing synaptic architecture, host defense, and myelin, respectively), are now thought to be highly integrated into the pain process, particularly with regards to chronic pain. Recently described is the tetrapartite synapse, which includes an astrocyte, microglial cell, and pre- and post-synaptic neuronal terminal. A recently isolated chemokine, fractalkine, appears to be a neuron-glial cell signal, activating glially-dependent pain facilitation (in a recent rat model, blocking the one known fractalkine receptor in rats diminished the development of neuropathic pain). Indeed, the glia may play a primary role with regards to synaptic strength, plasticity, and sensitization in the spinal cord, which does exhibit substantial change under the influence of chronic pain.

Other Investigative Drug Targets

     • specific subunits of the NMDA-receptors (eg, NR2B receptor antagonists)

     • cannabinoid receptor agonists

     • neurokinin-1 (NK-1) antagonists

     • nerve growth factor (NGF antagonists)

     • Substance P

Genes

Ultimately, the highest hopes for targeted, highly condition- and patient-specific treatment interventions lie in unraveling the mysteries of gene expression. The genes involved are most likely numerous, each with a small but highly interactive, summating effect, rather than a few genes with major effects. Currently in people as well as animals, we are mostly in a position of using broad-based modalities, using best available evidence to help the largest number of patients with the least adverse effects. But genetic factors explain a significant amount of the biological variation in pain-related behavior and psychophysiological processes. Heritability accounts for 35-68% of the most common chronic pain conditions in humans (e.g. shoulder/elbow, neck/low back, migraine), with environmental factors accounting for the rest. Recent work also demonstrates genetic variability in response to therapy; in humans, for example, a recent study showed that opioid efficacy can be predicted based on various gene expressions. Other studies demonstrate heritable differences in the gene that codes for certain cytochrome P450 enzymes (or inheriting multiple copies of it!) that can result in poor, or conversely ultra-rapid drug metabolism, which would have a direct impact on dosing such classes of drugs as opioids, tricyclic anti-depressants, and others.

The genetic influence is broadly defined into "pain mechanism" genes (those that mediate the pain pathways) and "pain susceptibility" genes (those that contribute to variation in response to painful stimuli and neuropathic pain). Aberrations in pain mechanism genes would likely be very uncommon, since pain is necessary for survival, and indeed major impairments of nociception, such as hereditary sensory and autonomic neuropathy (HSAN, formerly called anhydrosis) are quite rare. Thus research attention is concentrated on the polymorphisms of pain susceptibility genes. Novel analgesics will likely target an individual protein, cytokine, or neurotransmitter expressed by a particular patient with a particular condition at a particular time (many genes change expression – or are newly expressed - in sensory neurons after inflammation and along the continuum of pain pathological states).

Future work in this area holds the promise of highly effective individualized therapy with wide margins of safety. Already a Pain Genes Database is being compiled (of the mouse genome) that will increasingly speed illumination and understanding of the genetic basis of pain. As stated by Dr. Daniel Carr, editor of the International Association Study of Pain Clinical Updates, "Optimal pain control may be achievable through understanding of molecular-genetic mechanisms, yielding individualized analgesic medications and dose regimens based upon each person's genetic endowment."

Therapeutically, the ability to control gene expression is termed "Genomics", in which several aspects of not just whether a gene works or not, but how it does so: "transcriptomics," "proteomics", and "metabolomics."

In veterinary medicine, one diet formulation has been purported to leverage "nutrigenomics" into a therapeutic strategy for weight loss.

Nutrition

There is growing acceptance of the important role nutrition plays in the maintenance of bone and joint health. For example, articular cartilage is critically dependent upon the regular provision of glucose, amino acids, vitamins (particularly vitamin C), and essential trace elements (zinc, magnesium, and copper), and imbalances may be involved in the pathogenesis of osteoarthritis. Omega-3 polyunsaturated fatty acids exert their action through competitive inhibition of pro-inflammatory prostaglandin production. 33% of Americans who use complementary modalities cite pain as the reason for doing so, and omega-3 PUFA's remain one of the more well-studied modalities. Recent evidence in humans strongly suggests that omega-3 PUFA's are an attractive adjunct for treatment of inflammatory joint pain; similar results are being demonstrated in canine osteoarthritis. Other nutritional supplements such as SAMe, melatonin, and others are receiving attention for their pain-mitigating effect.

Autologous Adipose-derived Adult Stem Cell Transplantation

A new technology emerging in both human and veterinary medicine, this modality holds great promise and is well within the scope of the primary care clinician to master. Certification to perform the procedure is available through www.vet-stem.com

Future therapies in veterinary medicine may include the use of invasive techniques already commonly employed in human medicine; examples include regional blockade, local anesthetic infusion units, epidural catheter placement, and ablation techniques. Increasing usage of minimally-invasive surgical techniques are being driven by primary care clinicians. Non-invasive modalities will include greater availability and use of physiotherapy techniques already currently in use, and the introduction of others mostly found currently in human medicine. Examples include pulsed radiofrequency, possibly (conflicting data at this time) therapeutic laser, , , electromagnetic field therapy, and others.

Do Animals Get....?

Many well-recognized pain syndromes in humans are yet to be recognized in dogs and cats but there is no reason to believe that they do not exist...consider the simple tension headache. Other commonly recognized syndromes in people include:

     • Migraine headache

     • Cluster headache

     • Post-herpetic Neuralgia

     • Diabetic Neuropathy

     • Trigeminal Neuralgia

     • Tempormandibular Joint Dysfunction

     • Fibromyalgia

     • MFS (Myofascial Pain Synd.)

     • Facet pain

     • Lumbar radicular pain

     • Complex Regional Pain Syndrome

The capacity to measure pain will become more sophisticated, as more validated observational pain scoring techniques are developed. But the holy grail will be a biological marker or physiologic meter that will measure pain in more objective manners. Already, palpometers and response to quantitative stimulatory testing techniques are being employed in the research (and human clinical) setting .

The presence of pain elicits a constellation of variable – and likely patient-specific – changes in gene, neurotransmitter, and receptor expression, what is called the "neurobiological signature" of a particular condition. Future efforts will focus on the development of interventions that target the particular signature, and ultimately, for a particular patient.