Opioid pain

OPIOID FOR USE AS AN ANALGESIC IN DOGS

Pharmacology

Pain is the unpleasant sensation accompanying the majority of medical conditions; therefore the treatment of pain is one of the most essential and widely studied fields in pharmaceutical research (Rang, H.P. et al. 2007). Analgesics are agents that act on the nervous system to decrease perception of pain (Lemke, T.L et al. 2008). Opioids are a versatile group of opium alkaloids, synthetic derivatives related to these alkaloids are numerous natural and synthetic peptides which produce morphine-like pharmacological results (Lemke, T.L et al. 2008). Opioid Analgesics are all chemically related to the purified compounds extracted from the Papaverum somniferum poppy plant (Tranquilli, W.J. et al. 2007), they stimulate a broad range of central effects (Neal,M.J. 2002). The purified agents are known as opiates, many synthetic and semi-synthetic analogues are developed for use clinically (Tranquilli, W.J. et al. 2007). One of the first compounds to be structurally modified was morphine (Lemke, T.L et al. 2008). Alterations in opioid chemical structure can yield more potent agents with a greater affinity for specific analgesic receptors (Lemke, T.L et al. 2008). Their extensive treatments of pain consist of perioperative care, acute trauma patients, and long term application for those suffering chronic pain (Tranquilli, W.J. et al. 2007). This essay will look into the various classes of opioids and how their pharmacokinetic and pharmacological differences influence their analgesic activity when administered in dogs.

Opioids bind to proteins known as opioid receptors, instigating a biological response (Lemke, T.L et al. 2008). The three main receptors acted upon by opioids are mu(µ), delta (δ) and kappa (κ), all are found in spinal cord tissues and brain, each playing a role in pain intervention (Lemke, T.L et al. 2008). All three have considerable structural homology, thus it is probable that there exists a high degree of receptor interaction amongst various tissues (Tranquilli, W.J. et al. 2007). Mu receptors mediate the majority of clinical analgesic effects of opioid drugs, weak analgesics tend to act on δ-receptors, and are capable of modifying µ receptor-mediated antinociception (Tranquilli, W.J. et al. 2007). Currently only µ and κ agonists are used clinically in opioid analgesics (Lemke, T.L et al. 2008).

The discovery of µ, δ and ĸ receptor subtypes account for opioid receptor diversity (Tranquilli, W.J. et al. 2007). Pharmacological studies show there to be at least three µ-receptor subtypes; two δ-receptor subtypes; and as many as four subtypes for ĸ-receptor. (Tranquilli, W.J. et al. 2007). Each receptor subtype produces ranging degrees of analgesia, and CNS depression as well as potential for tolerance. Modification of their structures, allows the alteration of drug properties to create agents with different levels of duration and bioavailability (Lemke, T.L et al. 2008). The identification of these subtypes led to the possibility of developing subtype-specific therapeutic drugs; however such receptor subtypes functional significance remains unclear (Tranquilli, W.J. et al. 2007). The subtypes could be known receptors coupled to various signal transduction systems (Lemke, T.L et al. 2008).

Opioid receptors are disseminated widely in the brain; as intrathecal opiate administration in small doses results in analgesia, a central action for their effect is implied (Rang, H.P. et al. 2007). These opioid receptors belong to a super family of membrane-bound receptors coupled to G-proteins (Tranquilli, W.J. et al. 2007); all three subtypes reduce the intracellular cAMP content via adenylyl cyclase inhibition, as well as altering pathways for protein phosphorylation (Rang, H.P. et al. 2007). These receptors share a similar structure and function to receptors for other neuropeptides and neurotransmitters which act to regulate nerve cell activity (Tranquilli, W.J. et al. 2007). Opiates promote the opening of potassium channels through the activation of several types of G proteins (Tranquilli, W.J. et al. 2007), and thus prevent voltage-gated calcium channels opening; these main effects are seen at the membrane level (Rang, H.P. et al. 2007). A decline in Ca2+ influx at the pre-synaptic level will diminish release of transmitter substances, morphine preventing the release of substance P from primary afferent terminals of the dorsal horn neurons (Rang, H.P. et al. 2007),inhibits synaptic communication of nociceptive input (Tranquilli, W.J. et al. 2007)(see 3). These membrane effects result in reduction of neuronal excitability, inhibition of ascending nociceptive pathways and transmitter efflux (Rang, H.P. et al. 2007) (Tranquilli, W.J. et al. 2007).

Another mode of opioid action acts on the periaqueductal gray matter, upregulation supraspinal descending antinociceptive pathways (Tranquilli, W.J. et al. 2007). This is influenced by GABAergic neuronal mediated tonic inhibition, activation of opioid receptors have demonstrated suppression of such inhibitory affects (Tranquilli, W.J. et al. 2007). This cellular response triggers µ-receptors activating K ions present on presynaptic GABAergic nerve terminals inhibiting the release of γ-aminobutyric acid into the synaptic cleft (Tranquilli, W.J. et al. 2007). All three opioid receptors mediate similar effects, yet heterogeneous distribution of the receptors allows specific neurons to be selectively affected (Rang, H.P. et al. 2007). Morphine is capable of reducing the conduction of nociceptive impulses via the dorsal horn (Rang, H.P. et al. 2007) (Freye, E and Levy, J.V. 2008).

Full or pure opioid agonists are capable of producing maximal activation when binding to opioid receptors, leading to downstream processes and peak analgesia (Tranquilli, W.J. et al. 2007). The majority of typical morphine-like drugs are pure agonists, all of which have high affinity for µ receptors, and commonly lower affinities for δ and ĸ locations (Rang, H.P. et al. 2007)(see Table 2).

Morphine acts as a full agonist on all three types of opioid receptors Tranquilli, W.J. et al. 2007). No other drug has proven to be more efficacious at suppressing pain than morphine, even with the existence of more potent drugs and those which may produce more desirable characteristics in specific situations (Tranquilli, W.J. et al. 2007). As morphine is relatively hydrophilic is crosses the blood-brain barrier at a slower rate than Fentanyl, resulting in a delayed peak of activity even when administered intravenously (IV) (Tranquilli, W.J. et al. 2007). Perioperative use of morphine enables the management of pain relative to surgical procedures in canines (Tranquilli, W.J. et al. 2007). The detection of µ opioid receptors in the periphery has guided clinical practice to locally introduce morphine at sites of inflammation in canine joints enhancing analgesia (Tranquilli, W.J. et al. 2007) (see Table 1).

Although codeine is more reliably orally absorbed than morphine, its analgesic potency is only 20% or less so is mainly used for mild pain treatment (Rang, H.P. et al. 2007).When the dose levels increase, the analgesic potency remains constant (Rang, H.P. et al. 2007). The function of codeine is brought about by the substitution of a methyl group onto morphine; this modification limits the first-pass hepatic metabolism, high bioavailability (Tranquilli, W.J. et al. 2007). Morphine and codeine have similar degree of respiratory depression, but it is rarely a problem in clinical practice as it has a limited response at high doses (Rang, H.P. et al. 2007)(see Table 1).

Fentanyl is a µ opioid agonist with high lipid solubility and potency (Tranquilli, W.J. et al. 2007), its onset is faster than morphine's, yet has a shorter activation period (Rang, H.P. et al. 2007). As Fentanyl only has a short period of action it is normally given as a continuous injection to relieve pain (Tranquilli, W.J. et al. 2007). Clinically Fentanyl is most frequently used in dogs but does have analgesic potential in other species (Tranquilli, W.J. et al. 2007). Fentanyl patches are applied to the canine skin for the direct and rapid treatment of severe pain (Rang, H.P. et al. 2007). In just five minutes after administration the peak analgesic effects are reached, lasting roughly 30 minutes (Tranquilli, W.J. et al. 2007).The drug is rapidly redistributed to inactive tissues, causing a decline in plasma concentration levels, therefore is accountable for the swift termination of clinical consequences (Tranquilli, W.J. et al. 2007) (see 4).

Methadone is used for addiction of morphine, when administered together morphine is incapable of eliciting its normal level of euphoria (Rang, H.P. et al. 2007). Although methadone has pharmacological similarities to morphine (Tranquilli, W.J. et al. 2007), the major difference is its considerably longer duration of action, with less sedative results (Rang, H.P. et al. 2007). The drug binds in the extravascular compartment so exerts a slow release (Rang, H.P. et al. 2007). The drug is used primarily in humans to suppress opioid withdrawal symptoms; however its potential in chronic pain therapy is being increasingly identified (Tranquilli, W.J. et al. 2007).

These drugs combine a measure of agonist and antagonist interactions with different receptors (Rang, H.P. et al. 2007). Buprenorphine is a semi-synthetic opioid that is highly lipophilic (Tranquilli, W.J. et al. 2007), it acts as a partial agonist when bound to µ receptors (Rang, H.P. et al. 2007), yet it exerts antagonist effects when acting on ĸ receptors (Rang, H.P. et al. 2007). In the presence of δ receptors this drug has a weak or no consequence, exhibiting a varied selectivity for receptor subtypes (Rang, H.P. et al. 2007). These drugs may be inadequate at treating severe pain (Tranquilli, W.J. et al. 2007). With a high affinity for µ receptors it eagerly binds to them then slowly dissociates, but is unable to produce a maximal clinical response, proving difficult to reverse its actions with naloxone (Tranquilli, W.J. et al. 2007). Buprenorphine activity persists for 8-12hours, yet this rarely passes 6 hours in practice (Pascoe, P.J. 2000). In dogs the usage of buprenorphine is most effectively seen during the post-operative period, suppressing mild to moderate pain (Tranquilli, W.J. et al. 2007). If the dose is increased above the recommended level, a reduced analgesic effect may be produced (Pascoe, P.J. 2000) (see 5 + 6).

Antagonists have a high affinity for opioid receptors and capable of displacing agonists from µ and ĸ receptors, competing for their active sites (Tranquilli, W.J. et al. 2007). Nalaxone is the most important antagonist; it produces insignificant effects when administered alone, when combined it inhibits opioid activity (Rang, H.P. et al. 2007). Naloxone increases the body's responsiveness to stimuli, and potential to have greater perception of pain. (Tranquilli, W.J. et al. 2007). The uses of antagonists are only employed in emergency situations where respiratory depression is profound (Tranquilli, W.J. et al. 2007). Routine use of antagonist opioids to reverse excess sedation in patients is likely to cause pain via the activation of the sympathetic nervous system (Tranquilli, W.J. et al. 2007). Naloxone in dogs is metabolized to naloxone glucuronide (Pascoe, P.J. 2000). It only provides effective antagonism for about 1 hour, due to its relatively slow half life in the brain (Pascoe, P.J. 2000). If it persisted longer the animal may regress to the effects of agonist. Intravenous doses are said to last 30-60 minutes, close observation for renarcotization of veterinary patients is required after each dose (Tranquilli, W.J. et al. 2007) (see 7).

Individual patient variability exits in both humans and dogs regarding oral absorption of morphine formulations (Aragon, C.L. et al. 2008). Orally administered opiates are typically attributed to pre-systemic metabolism for low systemic levels, thus extensively metabolises the drug with hepatic and intestinal enzymes (Aragon, C.L. et al. 2008). This occurs foremost in canine species, the liver in dogs is the primary metabolising organ for morphine (Aragon, C.L. et al. 2008). It is absorbed from the GIT, and its conjugation produces morphine-3-glucuronide (M-3-G) making up to 60% of the administered dose (Mather, L.E. 2001) and M-6-G (Aragon, C.L. et al. 2008). On its own M-3-G has no analgesic effect, in animal models it antagonises morphine's antinociception (Mather, L.E. 2001). M-6-G is similar to morphine producing analgesia (Mather, L.E. 2001). The accumulation of metabolites in the CNS is thought to play a role in CNS irritability syndrome and opioid tolerance (Mather, L.E. 2001).Codeine derived opioids have a blocked 3-OH group demonstrating adverse effects including tolerance (Mather, L.E. 2001).

Dependency is encompassed of two components; psychological cravings lasting as long as years; and physical short lived withdrawal symptoms only persisting a few days. Drug dependency is relieved by µ-receptor agonists such as methadone, so the presence of µ-receptor antagonist results in withdrawal symptoms (Rang, H.P. et al. 2007).Tolerance rapidly develops due to continual administration of opioids (Neal,M.J. 2002) and is followed by physical withdrawal syndrome (Rang, H.P. et al. 2007). Tolerance is not pharmacokinetic in origin, and down regulation of the receptor is not a main contributing factor, leaving its mechanism unclear (Rang, H.P. et al. 2007).

A patient experiencing pain is complex, as the opioid drugs do not produce the same effects in every patient. The effects must be specific, with a balance between therapy and adverse effects (Mather, L.E. 2001). Various opioids will exert their effects relative to the affinity for their specific receptors (Rang, H.P. et al. 2007). Pain management in dogs is diverse and dependent upon the animal's requirements and severity of pain. It is most important to observe the patient, to ascertain the level of pain, and with that information drugs, administration, and dosage therapy programmes can be adjusted accordingly (Mather, L.E. 2001). Extensive therapy with opioids can lead to tolerance, and dependency resulting in withdrawal symptoms (Rang, H.P. et al. 2007). It is essential to manage opioids to prevent their abuse and environmental pollution by excessive veterinary treatments (Neal,M.J. 2002).

References

Aragon, C. L., Read, M. R., Gaynor, J. S., Barnhart, M. D., Wilson, D., Papich, M. G (2008) Pharmacokinetics of an immediate and extended release oral morphine formulation utilizing the spheroidal oral drug absorption system in dogs, J. vet. Pharmacol. Therap. 32; 129-136.

Chahl, L. A. (1996) Opioids, mechanisms of action, Australian Prescriber, 19; 63-5.

Finkel, R., Clark, M.A., Cubeddu, L.X. (2009) Pharmacology 4th ed. Lippincott Williams & Wilkins ISBN 0-7817-7155-9

Fish, R.E., Brown, M.J., Danneman, P.J., Karas, A.Z. (2008) Anaesthesia and Analgesia in laboratory animals, 2nd ed. Elsevier ISBN 978-0-12-373898-1

Freye, E., Levy, J.V. (2008) Opioids in medicine, a comprehensive review on the mode of action and the use of analgesics in different pain states, Springer Science, ISBN 978-4020-5946-9

Lemke, T.L, Williams, D.A. (2008) Foyle's principle of medical chemistry 6th ed. Lippincott Williams & Wilkins ISBN 978-0-7817-6879-5

Mather, L.E. (2001) Trends in the pharmacology of opioids: implications for the pharmacotherapy of pain, European Journal of Pain 5; 49-57

Neal, M.J. (2002) Medical pharmacology at a glance, 4th ed. Blackwell Science ISBN 0-6-32-05244-9

Pascoe, P.J. (2000) Opioid analgesics, Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, California, 30; 757-72.

Rang, H.P., Dale, M.M., Ritter, J.M., Flower, R.J (2007) Rang and Dale's Pharmacology, 6th ed. Elsevier ISBN 0-443-06911-5.

Tranquilli, W.J., Thurmon, J.C., Grimm, K.A (2007) Lumb & Jones Veterinary anaesthesia and analgesia, 4th ed., Blackwell Publishing ISBN 978-0-8138-2566-3.

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