Opioids: the good, the bad? and the future (Proceedings)

Synthetic opioids are powerful, useful tools to manage pain for one simple reason: Receptors for naturally-occurring opioids (endorphins, enkephalins) are distributed ubiquitously throughout the body and can be found in both central and peripheral tissues. Several opioid different receptor types and subtypes have been isolated, each with a variant effect. The historic categorization of mu, kappa, delta, and sigma opioid receptor subtypes have been re-classed according to a rubric aligned with gene expression. However for the sake of our discussions, this manuscript to familiar and traditional Greek-letter categories, and in particular mu and kappa receptors as these are the two that are manipulated in animals to provide analgesia.

Activation of a mu-opioid receptor inhibits presynaptic release (especially in the dorsal horn of the spinal cord) and postsynaptic response (especially in the dorsal root ganglion) to excitatory neurotransmitters. The proposed mechanism includes opioid receptor coupling with the membrane-associated G protein; this leads to decreased intracellular formation of cAMP which diminishes calcium channel phosphorylation (closing off the voltage-gated calcium channel) and opens potassium channels enhancing potassium influx. The resulting effect is hyperpolarization of the neuron and blockade of Substance P release. Nociceptive transmission is thus greatly impeded.

Opioid tolerance and resistance occurs when signaling cascades force calcium channels to remain open despite the presence of opioid. Additionally, glial cells, once thought to merely provide supporting roles in the spinal cord but are now known to be highly interactive with nociceptors, dysregulate opioids...and unfortunately, opioids activate glial cells. Therefore in an important sense, the pain we perceive is a balancing act between the activity of the opioids and the activity of glia.

A number of different opioid drugs are available which vary in their relative potency and receptor affinity.

Pure MU-agonists:

Morphine remains the prototype opioid and the opioid in widest use; it has no ceiling effect on analgesia or respiratory depression, elicits histamine release, and causes vomiting at low doses (higher doses, IV doses, and chronic use do not elicit vomiting, presumptively by interaction with mu receptors in the antiemetic center). Cats lack glucoronate metabolism, resulting in minimal production of the analgesic M6G metabolite, therefore morphine may not be the ideal opioid for use in this species.

Oxymorphone (Numorphan®) and hydromorphone (Dilaudid®) do not elicit histamine release (therefore may be wiser choice in cases of hypovolemia e.g. trauma, dehydration), and nausea may be less pronounced, but they have a much shorter duration of action than morphine; also, hydromorphone in particular is implicated in episodes of hyperthermia in cats.

Methadone may also be an attractive opioid alternative in animals, in part due to its additional effect as an NMDA antagonist and evidence of effectiveness in rodent models of neuropathic pain. The parenteral preparation is favored by some veterinarians as a pre-medication due to its low AE profile (minimal if any nausea, no histamine release) and prolonged sedative properties. Orally, however, in contradistinction to humans, it appears to have low oral bioavailability and rapid clearance.

Fentanyl is a short-acting opioid preparation (Sublimaze®) with a potency of 80-100x that of morphine. It is most often used in as an intravenous constant rate infusion. Fentanyl in a transdermal patch (Duragesic®) remains useful in veterinary medicine though a number of studies have demonstrated wide kinetic variability in veterinary patients due to species, body condition score, body temperature, surgical procedure, where and how well the patch is placed, etc.,

Meperidine (Demerol®) is a weak mu-agonist (approx. ¼ the potency of morphine) but more importantly carries a very short duration of action in the dog (less than 1 hour). These features have limited its use in animals.

Commercial oral opioid preparations are widely available, and while there is often a significant first-pass effect limiting bioavailability, these drugs are not without their utility. Hydrocodone, codeine (both alone and in combination with acetaminophen), hydromorphone (Dilaudid®) and sustained-released forms of oral opioids include morphine (MSContin®), oxycodone (Oxycontin®), and oxymorphone (Opana ER®) are all available by prescription. PK data exists for some of these formulations but PD (efficacy) data is currently lacking in dogs and cats. Oral methadone in humans has much higher bioavailability (>70%) than does morphine (<20%), but in dogs the oral bioavailability of methadone appears to be very low. Transmucosal preparations such as fentanyl buccal tablets and suckers (Actiq®, Fentora®) do exist, but pharmacokinetics and pharmacodynamics in dogs and cats is less established and the limitation of administration to dogs and cats of this kind of delivery system is self-evident. Rectal suppository opioid formulations may also be prescribed, but appear to provide little advantage in bioavailability over the oral route in the dog.

Tramadol has also become a popular adjunct to chronic pain management in both human, and veterinary medicine because of its effectiveness as a weak opioid, and norepinephrine and serotonin (an inhibitory neurotransmitters) agonist. However, conversion to the active mu agonist M1 metabolite appears to be minimal in the dog, indicating most of its activity in this species may be derived from its seritoninergic and noradrenergic activity. Per-rectal administration does not appear to offer an advantage in this regard. Tapentadol (Nucytna®) is a new centrally acting analgesic with a dual mode of action similar to tramadol: mu-opioid receptor agonism and inhibition of norepinephrine reuptake. However, it is the parent compound, not a metabolite, that provides for both of these effects, and thus may offer an alternative superior to tramadol in dogs. Tramadol (and tapentadol) should not be used with other serotoninergic medications such as tricyclic antidepressants, SNRI's, and amitraz-containing compounds.

Partial MU agonist

Buprenorphine (Buprenex®) is a partial agonist on the mu receptor though it has greater affinity than morphine (and will displace it if given together). A great benefit of the drug in veterinary medicine is that its pKa (8.4) closely matches the pH of the feline oral mucosa (9.0), which allows for nearly complete absorption when given buccally in that species, with kinetics nearly identical to IV and IM administration, and eliciting very little sedation. Transmucosal absorption in the dog appears to be much lower than in cats (approx. 40% ), indicating the utility of TM buprenorphine was limited, albeit present, in this species. Buprenorphine does have a ceiling effect.

Agonist-antagonist

Butorphanol is a weak mu antagonist and a kappa agonist; while it will weakly block the mu-opioid receptor (reversing the effects of any of the mu-agonists, if present), the kappa agonism will promote the release of inhibitory neurotransmitters such as GABA. Its very short duration of action in the dog (approx. 30-40 min, though sedation may be longer) makes it a poor choice for an analgesic in this species for any kind of significant or prolonged pain states, though used parenterally it has utility as an adjunct with other medications such as alpha-2 agonists. It comes as both a parenteral and oral formulation. Nalbuphine is an injectable mu-antagonist, kappa agonist (and currently not controlled). One recent study in humans reports success with repeated weekly injections in relieving patients previously suffering from refractory chronic pain.

Antagonist

Naloxone (Narcan®) is a potent mu-opioid receptor antagonist, traditionally used to achieve rapid reversal of opioid overdose or opioid-induced severe adverse effects. However, the reversal of opioid AE in veterinary patients is often accomplished instead with the use of a partial mu agonist such as buprenorphine or a mu-antagonist/kappa agonist such as butorphanol; this allows the AE to diminish while maintaining a degree of analgesia. Interestingly however, in humans, micro-doses (as low as 0.01 – 0.05 mcg/kg IV) of naloxone have been used to improve the analgesia provided by buprenorphine.

New formulations of opioids may overcome the need for, and limitations of, intravenous CRI opioid administration, fentanyl patches, and PO administration. These long-acting technologies in development include liposome-based formulations and novel delivery systems.

Opioids for all their effectiveness may create clinical challenges as well. In the acute setting, opioid-induced dysphoria, hyperalgesia, and respiratory depression may be encountered; recognizing and having strategies for counteracting their signs will minimize the complications that they present. In the chronic setting, currently infrequently utilized in veterinary medicine (arguably inappropriately so), the most commonly reported in humans by far is constipation; but abnormal pain sensitivity, hormonal changes, and immune modulation are also reported though their mechanisms are not fully established.

Fortunately, novel Peripherally Acting Mu Opioid Receptor Antagonists (PAMOR) are in the final stages of development; taken with an oral opioid, PAMORs will permit the central analgesic effect of the opioid but block their effect on gastrointestinal motility. Additionally, microdoses of the mu-antagonist naloxone added to patient morphine PCA have diminished opioid-associated adverse events. Such medications hold great promise in minimizing constipation and other peripheral AE's, which commonly forces the withholding of opioids.

A final word on newly-illuminated confounders to opioid effectiveness and the development of opioid tolerance and resistance. Several drugs are being actively investigated for their anti-glial activity, and we can likely expect to see them in common use with opioids.

Adopted From: Your Patient Is Still In Pain—Now What? "Rescue Analgesia" (S7AP) WVC 2009 Posner LP, DVM, DACVA; Papich, DVM, DACVCP

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