Analgesic Drugs in Animals--Why Animals are Different from People
World Small Animal Veterinary Association World Congress Proceedings, 2007
Mark G. Papich, DVM, MS, DACVCP
Professor of Clinical Pharmacology, North Carolina State University
Raleigh, NC, USA

Veterinarians are familiar with the use of the various injectable analgesic drugs available in the hospital. Potent injectable opiates, alpha-2 agonists, local anesthetics, and other combinations are available to veterinarians. These drugs have improved treatment of acute pain. However, what can we do about treatment of chronic pain when injectable opiates are not practical? Cancer pain, back pain, osteoarthritis, and neuropathic pain are among the conditions requiring treatment at home. Post-operative pain treatment during recovery from surgery also may require medications administered by pet owners. NSAIDs are usually the first line of therapy, but some conditions may not be controlled by NSAIDs alone, and some patients may not tolerate NSAIDs because of adverse effects. What drugs are available for pet owners to administer out of the hospital, used in combination with other medications--including NSAIDs--or alone?

Morphine

Morphine is the prototype of opiate analgesics. One of the metabolites is morphine-6-glucuronide (M6G), which is active. In people it is produced by first-pass metabolism from an oral dose. That is, as the drug is absorbed from the gastrointestinal tract, enzymes in the liver (and perhaps intestine) convert the drug to an active metabolite (Babul & Darke 1993). Although evidence is variable, some studies have shown that the M6G metabolite may be more effective as an analgesic than the parent drug. Oral morphine is available as syrup, tablets, and prolonged-release oral medications. Oral morphine has been administered in some veterinary hospitals by prescribing the oral extended-release morphine such as MS Contin. But extended-release morphine did not produce significantly longer plasma levels than immediate release tablets and absorption is low and variable (Dohoo & Tasker, 1997). One study recommended starting with an oral morphine dose of 15 mg/dog every 8-12 hours (Dohoo 1997). The assay used in these studies did not differentiate active from inactive forms of morphine. Despite the potential advantages of oral morphine formulations, pharmacokinetic studies to demonstrate effective blood concentrations of active drug or metabolites from extended-release morphine tablets are lacking. Studies at NCSU showed that oral absorption of morphine is negligible in dogs and they did not produce the active metabolite (M6G). These studies used a specific assay that differentiated morphine and the glucuronides from inactive metabolites (KuKanich et al, 2005). When the immediate-release morphine tablets were given to dogs, they vomited and failed to produce detectable concentrations. Therefore the efficacy of oral morphine in dogs is questionable due to high clearance and poor oral systemic availability. To our knowledge, oral morphine has not been evaluated in cats. However IV clearance is high and there is little M6G produced in cats (Taylor et al, 2001). This suggests that oral administration of morphine to cats may not produce beneficial effects.

Oxymorphone

In comparison to morphine, oxymorphone is approximately 10 to 15 times more potent when injected. There are several published studies using injectable forms of oxymorphone, but to our knowledge, no studies using oral or rectal routes of administration have been reported for dogs or cats.

Codeine

Codeine is relatively safe and inexpensive, but is comparably weak as an analgesic. In humans, approximately 10% of a dose of codeine is converted to morphine. In dogs, there is only limited evidence of oral absorption. It one study, oral absorption was estimated to be only 6.5% in dogs (Findlay et al, 1979). However, de-methylation to morphine (which is minor in dogs) may not account for codeine's efficacy. A 6-glucuronide metabolite may also contribute to its analgesia (Lötsch et al, 2006), and this route may be significant for dogs (Findlay et al, 1979). The metabolic pathways have not been investigated for cats.

Codeine is sometimes used by veterinarians for oral treatment of moderate pain. It is available as a 15, 30 and 60 mg tablet (codeine sulfate, codeine phosphate) and 5 mg/ml syrup. Some formulations are combined with acetaminophen and/or caffeine (For example, Tylenol-2 or -3). We are not aware of analgesic studies in dogs in which codeine was examined with or without acetaminophen.

Dextromethorphan

Dextromethorphan is not a true opiate, because it does not bind μ- or κ-opiate receptors. The most common use is as an antitussive in over-the-counter cough and cold medications (e.g., Robitussin, Vicks 44). Dextromethorphan is the d-isomer of levorphan (the l-isomer, levorphan is an opiate with addictive properties, but the d-isomer does not). Dextromethorphan produces mild analgesia and modulate pain via its ability to act as an NMDA (n-methyl D-aspartate) antagonist (Helmy & Bali, 2001; Pozzi et al, 2006), but this is unrelated to the antitussive action.

Dextromethorphan has been administered to dogs and cats, but recent pharmacokinetic studies in dogs indicated that dextromethorphan does not attain effective concentrations after oral administration (KuKanich & Papich, 2004). There are no injectable formulations available for clinical use. For one study, an IV formulation was prepared in the laboratory (KuKanich & Papich, 2004), which produced severe CNS reactions. Even after IV administration, concentrations of the parent drug and active metabolite persisted for only a short time after dosing. Therefore, routine use in dogs is not recommended until more data is available to establish safe and effective doses.

Butorphanol

Butorphanol has mixed opiate effects sometimes called an agonist/antagonist. Because of the mixed receptor binding, it may produce opiate effects that differ qualitatively from those of pure opioid agonists such as morphine. Such differences may include less respiratory depression, fewer psychotic effects, fewer hemodynamic effects, and less physical dependency. A ceiling on the analgesic effects (that is, a limit to the analgesic efficacy of these drugs), also distinguishes agonist/antagonists from pure opioid agonists.

Butorphanol produces its analgesic effects because of the activity as a kappa-receptor agonist. Although injections of butorphanol have been widely used in dogs, horses, cats, and some zoo and exotic animals, the efficacy of the oral formulation for treating pain has not been evaluated. It is available as 1, 5 and 10 mg tablets (Torbutrol). For the injectable form, efficacy is of short duration and limited to mild pain. Because of the short duration of action observed from injections of butorphanol, analgesic effects from an immediate-release oral tablet are expected to have limited effectiveness.

Buprenorphine

Buprenorphine (Buprenex) is a partial μ-receptor agonist, with little effects on the κ-receptor (Johnson et al, 2005). It is 25-50 times more potent than morphine and available as a 300 μg/ml injection. In animals it is reported that the duration of analgesia is longer (for example 6-8 hours) compared to the duration of action of morphine, perhaps because it dissociates slower from receptors. Because of these reports of a longer duration of activity, use of buprenorphine in dogs and cats has increased. In cats, buprenorphine was injected at a dose of 0.01 mg/kg with a duration of action between 4 and 12 hours (Robertson, et al. 2003). There also has been some at-home use (for example, post-operative) by oral administration. Systemic absorption is achieved by absorption via the oral mucosa (that is, the drug should not be swallowed). The oral (sublingual) dose for cats is 0.066 mL per kg (Robertson et al. 2003). Absorption was complete with plasma concentrations as high as the analgesic levels observed from injections. The pH of a cat's saliva favors this trans-mucosal absorption.

Other Opiates

Other drugs that have been considered, but have not been evaluated clinically in veterinary medicine include: oxycodone + aspirin (Percodan), oxycodone + acetaminophen (Percocet), hydrocodone (Hycodan), hydrocodone + acetaminophen (Vicodin), and sustained release oxycodone (OxyContin). These drugs are frequently used in people for treatment of chronic pain. They are highly addictive and a considerable amount of abuse occurs from prescriptions written for chronic use. Long-term prescriptions for dogs and cats are discouraged. Because of the previously-documented poor oral absorption of other opiates documented for dogs, the oral absorption of these drugs is also expected to limit their efficacy.

Tramadol (ultram)

Tramadol is an analog of codeine that has multiple effects. Although tramadol has opiate-mediated effects, it has low abuse potential and is not registered as a controlled substance. It has become available in generic form, and is inexpensive. The exact mechanism of action to explain tramadol's analgesic effects is uncertain. However, various possibilities exist: tramadol has mu-opioid receptor activity and it also inhibits the reuptake of norepinephrine (NE) and serotonin (5-HT) (Laugessen et al, 2005). One of the isomers has a greater effect on serotonin reuptake and greater affinity for mu-opiate receptors. The other isomer is more potent for norepinephrine reuptake and less active for inhibiting serotonin reuptake. The metabolite (desmethyltramadol, also called M1) may have greater opiate effects than the parent drug (for example, 200x in opiate receptor binding). Taken together, the effects of tramadol may be explained through inhibition of serotonin reuptake (similar to fluoxetine and other antidepressant drugs), action on alpha-2 receptors (similar to medetomidine and xylazine), and activity for opiate mu-receptors (similar to morphine). There is considerable support for the serotonergic effects being important for the analgesic efficacy of tramadol. It can induce changes in the CNS similar to that observed with conventional antidepressant drugs (Rojas-Corrales et al, 2005; Oliva et al 2002). The serotonin-mediated effects may be synergistic with the opiate-mediated effects from the active M1 metabolite (Rojas-Corrales et al, 2005).

Studies completed at NCSU (Kukanich & Papich, 2004) showed that tramadol is absorbed orally in dogs and was well-tolerated. They make sufficient metabolite (desmethyl metabolite also referred to as M1) that may produce analgesic effects. Clearance in dogs is higher than in people, requiring larger mg/kg doses. At this time, we are recommending doses of 5 mg/kg every 6 to 8 hours orally in dogs. Some dogs have responded to less frequent administration. The safety margin appears to be high based on clinical experience and studies performed in laboratory animals. There is an increased risk of seizures in people; therefore animals prone to seizures should be monitored closely. Tramadol should not be used with other drugs that affect monoaminergic systems (e.g., other antidepressants, selegiline).

Preliminary studies in cats indicate that they produce proportionately more of the M1 (opiate) metabolite than dogs. Therefore, in cats more opiate-related adverse effects are possible (excitement, dysphoria, mydriasis). There are anecdotal accounts of these effects occurring when cats have been administered doses as high as for dogs. Therefore, although there is not enough data to formulate dosage regimens for cats, until other information becomes available, we recommend that the doses should be lower than for dogs.

Tramadol (Ultram, and generic) is available in 50 mg immediate-release tablets. There also is an extended-release formulation for people (Ultram-ER). The tablets are 100, 200, and 300 mg, but they are expensive. The release is controlled with a coating, which allows once-daily administration in people. This coating delays the absorption in dogs until the tablet reaches the distal ileum or colon. This leaves little time for absorption to occur and the plasma concentrations attained are delayed and are only 25% after an equivalent dose in people.

Transdermal Drug Delivery

Transdermal delivery of potent opiates has been examined in several veterinary species. One such delivery device consists of a patch containing a reservoir of fentanyl (Duragesic) which is absorbed through the skin. Transdermal administration of fentanyl at a delivery rate of 100 μg/hr is therapeutically equivalent to intramuscular administration of 60 mg of morphine.

Use in Dogs. Experience at NCSU showed that the analgesia from a patch to dogs controlled postoperative pain as well as injections of oxymorphone (Kyles et al 1998). One patch (e.g., Duragesic-50) applied to the skin of dogs may provide analgesia for at least 72 hours. The dose delivered depends on the patch's surface area. Patches are available that deliver 25, 50, 75, and 100 μg/hr. Duragesic-50 patches are appropriate for dogs from 10-20 kg and perhaps larger dogs. The dose delivered may be variable among patients. For example, rate of release of fentanyl has varied from 27% to 98% (mean 71%) of the theoretical value (Kyles et al 1996). Because of this variability, clinical analgesic effects may not be observed in some patients. In these cases consider removing the patch and applying another, or switch to another drug.

Use in Cats. Research at NCSU showed that a Duragesic-25 patch appears to be appropriate for average size cats (Lee, et al 2000). Cats absorbed the fentanyl at an average rate of approximately that of the theoretical delivery rate, but one patch will maintain consistent concentrations of fentanyl in the plasma for at least 118 hours. Fentanyl delivered via this route has been well-tolerated in cats. Fentanyl patches (25 μg/hr) applied to cats were effective and safe to relieve pain from onychectomy surgery (Franks et al 2000), and ovariohysterectomy (Davidson et al, 2004). Cats that have received fentanyl patches have had improvement in temperament, attitude, and appetite. For small-sized cats, partial exposure of the adsorptive surface area of the patch will reduce systemic exposure (Davidson et al, 2004).

Other Non-opiated for Treating Chronic Pain

When chronic pain has not responded to traditional treatments other drugs and approaches have been attempted. Included in this list is amantadine, tricyclic antidepressants (clomipramine, amitriptyline), serotonin-reuptake inhibitors (fluoxetine, paroxetine), and gabapentin (Neurontin). Although there is significant clinical use of some of these medications, and anecdotal experience suggesting that they may be effective, there is little pharmacokinetic or pharmacodynamic data available for small animals. No clinical studies have yet been published documenting the effectiveness of these drugs in small animals.

References

1.  Babul N, Darke AC. Disposition of morphine and its glucuronide metabolites after oral and rectal administration: Evidence of route specificity. Clin Pharmacol Ther 54: 286-292, 1993.

2.  Davidson CD, Pettifer GR, Henry JD. Plasma fentanyl concentrations and analgesic effects during full or partial exposure to transdermal fentanyl patches in cats. J Am Vet Med Assoc. 2004 ;224(5):700-705.

3.  Dohoo SE: Steady-state pharmacokinetics of oral sustained-release morphine sulphate in dogs. J Vet Pharmacol Therap 20: 129-133, 1997.

4.  Dohoo SE, Tasker RA. Pharmacokinetics of oral morphine sulfate in dogs: a comparison of sustained release and conventional formulations. Can J Vet Res 1997;61(4):251-255.

5.  Findlay JW, Jones EC, Welch RM. Radioimmunoassay determination of the absolute oral bioavailabilities and o-demethylation of codeine and hydrocodone in the dog. Drug Metabolism Disposition 7: 310-314, 1979.

6.  Franks JN, Boothe HW, Taylor L, Geller S, Carroll GL, Cracas V, Boothe DM: Evaluation of transdermal fentanyl patches for analgesia in cats undergoing onychectomy. J Am Vet Med Assoc 217: 1013-1018, 2000.

7.  Helmy SAK, Bali A. The effect of the preemptive use of the NMDA receptor antagonist dextromethorphan on postoperative analgesic requirements. Anesth Analg 92: 739-744, 2001.

8.  Johnson RE, Fudala PJ, Payne R. Buprenorphine: considerations for pain management. J Pain and Symptom Management 29: 297-326, 2005.

9.  KuKanich B, Papich MG. Pharmacokinetics of tramadol and the metabolite O-desmethyltramadol in dogs. J Vet Pharmacol Ther. 2004 Aug;27(4):239-46.

10. Kukanich B, Papich MG. Plasma profile and pharmacokinetics of dextromethorphan after intravenous and oral administration in healthy dogs. J Vet Pharmacol Ther. 2004 Oct;27(5):337-41.

11. KuKanich B, Lascelles BD, Papich MG. Pharmacokinetics of morphine and plasma concentrations of morphine-6-glucuronide following morphine administration to dogs. Journal of Veterinary Pharmacology and Therapeutics. Aug;28(4):371-376, 2005.

12. Kyles A E, Hardie, E.M., Hansen, B.D., Papich, M.G. Comparison of transdermal fentanyl and intramuscular oxymorphone on post-operative behaviour after ovariohysterectomy in dogs. Research in Veterinary Science 1998; 65: 245-251.

13. Kyles AE, Papich MG, Hardie EM. 1996. Disposition of transdermally administered fentanyl in dogs. American Journal of Veterinary Research 57: 715-719.

14. Laugesen S, Enggaard TP, Pedersen RS, Sindrup SH, and Brøsen K. Paroxetine, a cytochrome P450 2D6 inhibitor, diminishes the steroselective o-demethylation and reduces the hypoalgesic effect of tramadol. Clin Pharm Ther 77: 312-323, 2005.

15. Lee DD, Papich MG, Hardie EM. Comparison of pharmacokinetics of fentanyl after intravenous and transdermal administration in cats. American Journal of Veterinary Research 2000; 61: 672-677.

16. Lötsch J, Skarke C, Schmidt H, et al. Evidence for morphine-independent central nervous opioid effects after administration of codeine: Contribution of other codeine metabolites. Clin Pharmacol Ther 79: 35-48, 2006.

17. Oliva P, Aurillio C, Massimo F, et al. The antinociceptive effect of tramadol in the formalin test is mediated by the serotonergic component. Eur J Pharmacol 445: 179-185, 2002.

18. Pozzi A, Muir WW, Traverso F. Prevention of central sensitization and pain by N-methyl-D-aspartate receptor antagonists. J Am Vet Med Assoc 228: 53-60, 2006.

19. Robertson SA, Taylor PM, Sear JW. Systemic uptake of buprenorphine by cats after oral mucosal administration. Vet Record 152: 675-678, 2003.

20. Robertson SA, Taylor PM, Lascelles BDX, Dixon MJ. Changes in thermal threshold response in eight cats after buprenorphine, butorphanol, and morphine. Vet Record 153: 462-465, 2003.

21. Rojas-Corrales MO, Berrocoso E, Micó JA. Role of 5-HT1A and 5-HT1B receptors in the antinociceptive effect of tramadol. European J Pharmacol 511: 21-26, 2005.

22. Taylor PM, Robertson SA, Dixon MJ, Ruprah M, Sear JW, Lascelles BD, Waters C, Bloomfield M. Morphine, pethidine and buprenorphine disposition in the cat. J Vet Pharmacol Ther 24(6):391-398, 2001.

Speaker Information
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Mark G. Papich, DVM, MS, DACVCP
North Carolina State University
North Carolina, USA


MAIN : Pharmacology : Analgesic Drugs
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