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

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Aug 01, 2010

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.