DOR-00043 TECHNICAL BULLETIN September 2018 Use of detomidine as a stand-alone equine sedative- analgesic: The Ohio State University 5-year clinical trial

Bimbo Welker, DVM, MS Department of Veterinary Preventive Medicine College of Veterinary Medicine The Ohio State University 16410 County Home Road Marysville, OH 43040

KEY POINTS • An obsolete concept in equine medicine, largely sustained by tradition and misinformation, is that multi-modal sedation-analgesia protocols for standing procedures are a superior alternative to stand-alone use of the alpha-2 agonist detomidine (Dormosedan®, Orion Pharma, distributed by Zoetis). • Disadvantages of the multi-modal approach are sometimes-severe side effects ofan opioid agonist/antagonist such as butorphanol, suboptimal depth or duration of effect, and inconvenience of combination dosing. • A 5-year clinical trial involving more than 1,500 horses at The Ohio State University determined that detomidine used as monotherapy for standing procedures was a superior alternative to multi-modal protocols for sedation and analgesia, or in comparison to monotherapy using other alpha-2 agonists. • The three alpha-2 agonists approved for veterinary use are not equivalent pharmacologically or in terms of their sedative and analgesic effects. At least three randomized, controlled studies have shown that detomidine provides substantially better sedation or analgesia than the other two. • Drug tolerance tests demonstrated that detomidine given at 5 times the maximum approved dosage for 3 consecutive days was well tolerated in healthy, mature horses, a result indicating that the highest approved dosage poses no safety hazard and that partial dosages provide no advantage. [Zoetis does not recommend the use of Dormosedan at higher than approved doses.] • Safety studies indicate that the physiologic effects of alpha-2 agonists including detomidine reach a self-limiting plateau whereby sedation and analgesia are prolonged but not increased. It is theorized that when the finite number of alpha-2 receptors become saturated, excess alpha-2 agonist molecules are not receptor-bound and therefore cannot exert a physiologic effect. This inherent safety mechanism is the probable basis for the essential non-toxicity of detomidine. • In more than 5 years of clinical use at The Ohio State University Large Animal Services clinic, a case fatality or serious adverse effect from detomidine given at any dosage has never occurred. Safe, effective, and reliable sedation is an benefit. In fact, investigators who evaluated essential part of equine practice. Not a day its analgesic effects in horses with tendon goes by when we do not sedate a horse at injuries noted that “detomidine deserves to the Ohio State University equine clinic. The be considered as a potent analgesic in the paramount goal of equine sedation is the horse rather than a sedative with analgesic safety of the clinician and other handlers, side effects.”1 Alpha-2 agonists have a who are typically working with a large, dose-dependent effect and are reversible, unpredictable animal. Sedation also ensures characteristics that contribute to efficient compassionate care of the horse and precise case management. Alpha-2 agonists are a control of the procedure being performed. non-narcotic, non-scheduled class of drug In modern practice, pharmacologic restraint requiring no special security or record is the clear preference over manual control, keeping. which is almost always less effective and Importantly, the three alpha-2 agonists conveys a less professional image. As a approved for veterinary use are not equivalent result, I consider the twitch and nose chain pharmacologically or in terms of their sedative that I carry in my truck to be supplemental and analgesic effects. For example, xylazine equipment, and I use them infrequently. has a much lower specificity for alpha-2 Equine sedation as practiced today is usually receptors (160:1) compared to detomidine accomplished using the extralabel use of (260:1) or romifidine (340:1).2,3 Relatively low combination protocols consisting of any of alpha-2 specificity increases the potential for several sedatives, tranquilizers and opioid aberrant effects caused by activity at non- analgesics, often given at reduced dosages alpha-2 receptor sites. Detomidine is also to moderate the possible side effects of 80-100 times more potent than xylazine and each. These agents generally include some has a longer duration of effect,4 reducing the combination of the alpha-2 agonist sedative- need for retreatment or supplementation. analgesics xylazine, detomidine, or romifidine; It is sometimes assumed that romifidine is the opioid analgesic butorphanol; the a newer, more advanced alpha-2 agonist phenothiazine tranquilizer acepromazine; because it is the latest drug in its class to or non-steroidal antiinflammatory drugs be approved for equine use. However, the (NSAIDs) such as flunixin. However, romifidine molecule was discovered in the for standing procedures in horses it is 1980s as a contemporary of detomidine, and my experience that stand-alone use of has only lately been commercialized in order detomidine is a superior alternative to multi- to participate in the alpha-2 agonist market. modal protocols for sedation and analgesia Randomized, controlled, double-blind studies or in comparison to monotherapy using other have shown that from a clinical standpoint alpha-2 agonists. An ongoing 5-year clinical detomidine is the most potent of the three trial at Ohio State involving more than 1,500 approved alpha-2 agonists: horses to date provides an evidence-based • Detomidine given IV at the approved rationale for this recommendation. This 20 and 40 mcg/kg doses provided bulletin discusses the results of the trial and substantially better sedation and why combination protocols for sedation often analgesia in horses compared to xylazine produce a less favorable clinical result than given at 0.5 mg/kg, butorphanol at 0.1 detomidine given as monotherapy. mg/kg, or the NSAID flunixin at 1 mg/kg.5 Advantages of alpha-2 • When compared to xylazine given at the maximum label dose of 1.1 mg/kg or agonists romifidine given at 2/3 the maximum When alpha-2 agonists became available dose, detomidine given at its lowest in veterinary medicine beginning with the approved dose (20 mcg/kg) was the only introduction of xylazine in 1969, clinicians one of the three alpha-2 agonists that for the first time had the ability to sedate provided statistically significant analgesia horses in a predictable way. Although they at 15 and 30 minutes after treatment.5 are primarily sedatives, alpha-2 agonists also • The sedation obtained with romifidine produce significant analgesia, a useful added was significantly shallower and 2 shorterlived than with detomidine at the limitations of xylazine and the desire to recommended doses, and detomidine augment sedation or analgesia provided by given at 10 mcg/kg (half the lowest any single drug overlooks the exceptional recommended dose) produced similar potency and specificity of detomidine. The effects to romifidine given at medium OSU clinical trial demonstrated that this and high doses of 80 and 120 mcg/kg, alpha-2 agonist provides reliable, dose- respectively.6 dependent sedation and significant analgesia, and is suitable as a monotherapy for virtually Origin and disadvantages of all standing procedures in equine patients. As multi-drug combinations’ an added benefit, sedation with an alpha-2 Given the dependability of the newer agonist is reversible in the few cases when alpha-2 agonists such as detomidine, why is this becomes expedient. combination treatment for equine sedation Detomidine misperceptions and analgesia so widely practiced? To a great extent, the limitations of xylazine, the original Because of the profound physiologic effects veterinary alpha-2 agonist, gave rise to multi- of detomidine derived from its exceptional modal treatment for sedation and analgesia. potency, a number of misperceptions have Xylazine is very short acting and delivers attached themselves to this product since its comparatively poor analgesia. As a result, it is U. S. introduction in the 1990s. These myths often necessary to supplement xylazine with include: other agents to get a satisfactory result or to • Always use a partial or minimal dose avoid re-dosing. A common early combination This is often interpreted to mean no was xylazine, acepromazine, and pentazocine more than 0.5 to 1 mL in an adult (Talwin), an opioid analgesic. A more recent (1,100-lb) horse, much less than the variation is a combination of xylazine, maximum approved dose of 2 mL per detomidine, and butorphanol, i.e., two alpha-2 1,100 lbs. This overabundance of caution agonists plus an opioid agonist/antagonist. probably originated with veterinarians The notion that multiple agents will provide who observed the adaptive bradycardia a synergistic or necessary supplemental resulting from peripheral vasoconstriction, sedative-analgesic effect is taught in our partial AV and SA blocks, and the veterinary schools and has become ingrained rapid, pronounced head drop following in veterinary practice. administration of detomidine. Inadequate However, there are disadvantages to the dose size is the single greatest deterrent multi-modal approach. Butorphanol induces to effective, stand-alone use of sometimes severe ataxia and head pressing,7 detomidine. creating a distraction when used for free- • The sedation lasts too long. This standing procedures. Part of the rationale observation was probably inspired by for combination dosing is that it supposedly xylazine’s comparatively short duration of justifies lower than recommended dosages of effect. I have found detomidine’s duration each individual agent. However, the result may of effect (30-90 minutes depending be sub-optimal depth or duration of sedation on dosage) represents little if any or analgesia. For example, in the case of disadvantage. detomidine significant sedation or analgesia • Onset of effect is slow. The myth that is not obtained until a dose of 20 mcg/kg is detomidine is slow acting may be the 8,9 reached. Lowering the butorphanol dosage result of partial dosing. In side-byside may mitigate ataxia and head pressing, but comparisons at our clinic, there was no at the cost of reducing the analgesic effect. difference in onset of effect of detomidine Finally, combination treatment sacrifices and xylazine when given at an equivalent simplicity and efficiency, particularly if re- per-weight dosage. Following IV dosing is needed. Stated another way, why administration, sedation occurs rapidly would a clinician use multiple drugs if one will with either drug, usually within 5 minutes. suffice? The viewpoint that xylazine works faster The multi-modal approach, based on the and detomidine lasts longer has given 3 rise to the unnecessary and extra-label hypertension was similar at all dosages, a practice of using both alpha-2 agonists in result reported by other investigators,11 as combination. was the degree of reduction in heart and • The horse may go down. In treating respiration rates. Only the duration of these more than 1,500 horses with detomidine, effects increased with dosage size. Benign sometimes at doses well above the conductivity disturbances such as second- highest approved level, I have only had degree AV and SA blocks, a class effect one horse become recumbent. That was of alpha-2 agonists, were reported at all a 29-year old mare with severe carpal dosages. Collectively, these results provided arthritis. She did not fall down, but laid assurance that full-dosage treatment with down, and later stood and resumed detomidine poses no safety hazard and that normal activity after the effects of partial dosages provide no advantage. detomidine had subsided. We have never Results of the safety tests confirmed that the had a case fatality in a horse treated with physiologic effects of detomidine, as in the detomidine. [Ed. note: FDA has reported case of other alpha-2 agonists, reach a self- death with the use of detomidine in their limiting plateau beyond which they do not Cumulative Veterinary Adverse Drug progress (Figure 1). When the finite number Experience (ADE) Reports database]. of alpha-2 receptor sites become saturated • It should be used at a partial dosage in a by an alpha-2 agonist such as detomidine, multi-modal combination. A widely used the maximum inhibition of norepinehprine is extra-label protocol is IV administration reached. The excess detomidine is not alpha-2 of 0.5 mL of detomidine (perhaps 25% receptor-bound, and theoretically exerts of the highest recommended dose for a no additional alpha-2 mediated physiologic 1,100 lb horse), 1.5 mL of xylazine, and 1 effect. Sedation and analgesia are prolonged mL of butorphanol. However, by simply but not increased when excess detomidine increasing the detomidine dose 2 to binds to alpha-2 receptors as they become 4- fold from the sub-optimal dosage, available. The plateau effect is the basis prompt, fully satisfactory sedation and for the essential non-toxicity and safety of analgesia will result, rendering a second detomidine. alpha-2 agonist and the opioid redundant We have demonstrated the detomidine and unnecessary. plateau theory in wet labs for the benefit of students or other practitioners. In these The plateau effect: The settings, I have intentionally given doses as inherent safety of detomidine large as 5 mL (2.5-fold times the maximum approved dose for a 1,100-lb horse) or used Target-animal safety studies described in the detomidine to continuously sedate a horse for detomidine freedom of information summary up to 4 hours with no adverse effects. [Zoetis provided an important basis for advocating does not recommend the use of Dormosedan full dosages of detomidine as a stand-alone higher than the approved dose.] treatment.10 Drug-tolerance tests showed that dosages of 200 mcg/kg (10 times the The clinical trial at Ohio State approved low dosage and 5 times the high dosage; approximately 10 mL for a 1,100-lb The impetus for conducting a long-term horse) given IV on 3 consecutive days were clinical evaluation of detomidine as a stand- well tolerated in healthy, mature horses. alone equine sedative was our dissatisfaction [Zoetis does not recommend the use of with one of the commonplace combination Dormosedan higher than the approved dose.] protocols – reduced dosages of xylazine and Microscopic foci of myocardial necrosis were detomidine given concurrently with a full dose identified at necropsy in only 1 of 8 horses of butorphanol. We modified the protocol given IV dosages of 400 mcg/kg (10 times the in stages. We first reduced the dosage of highest approved dosage) for 3 consecutive butorphanol and then eliminated it altogether days. However, cardiovascular function was to avoid the opioid-induced head-pressing not compromised in any of the horses given and ataxia. That left us with a protocol the 10-fold maximum dose. The degree of consisting of xylazine and detomidine. The 4 illogic of using two alpha-2 agonists at Dosing guidelines the same time led to the decision to use detomidine at its full, approved dosage as a In determining the appropriate detomidine stand-alone sedative-analgesic. dosage, I first categorize the horse by one of three temperaments – quiet, excited but We initiated an ongoing clinical trial of controllable, or agitated and fractious. Based detomidine at the Ohio State University on temperament, I then calculate a low, equine clinic beginning in April 2003. As medium, or high dose volume, usually within noted in Table 1, more than 1,500 horses the recommended dose of 20 and 40 mcg/ have been successfully treated to date kg. The dental-floating cases listed in Table with detomidine as monotherapy. About a 1 illustrate how the patient’s temperament third of these cases involved floating using determines detomidine dosage size for a motorized grinding tool (PowerFloat®, that particular procedure, and the relative Calgary, Alberta, Canada). Motorized floating distribution of cases for each temperament is an ideal application of standing sedation category. For example, for a 1,100-lb horse because the noise and vibration excite the with a quiet temperament, the average horse, the animal experiences some minor effective detomidine dosage for floating or discomfort, and the procedure takes place in a other dental procedures is 1.2 mL with a range restricted operating field. Enabled by sedation of 0.5 to 1.8 mL. In calculating the appropriate with detomidine, motorized dentistry can be a dosage, I estimate on the high side, which significant profit center for an equine practice, ensures complete sedation and minimizes the as it has been at our clinic. need for redosing. Table 1 lists other standing procedures that I generally prefer IV administration of we routinely performed using detomidine, detomidine, which gives the drug immediate including joint injection and laceration repair. access to the vascular bed, resulting in We have used detomidine successfully in a faster onset of effect. It is nonetheless horses up to 47 years of age, in all equine important to wait at least 5 minutes after IV breeds, and in mules and donkeys. The administration before initiating a surgical or dosage sizes shown in the table are calculated diagnostic procedure. If the clinician can wait using the recommended range of 20 to 40 as long as 15 minutes after administration, mcg/kg (0.2 to 0.4 mL per 100 kg or 220 lbs). that is when the most profound sedation

Proposed Detomidine Plateau Effect

D R R+D { α2 receptor-bound

D R R+D detomidine (R+D) D R R+D exerts sedative { effect D R R+D D D Excess detomidine is D D unbound and exerts no sedative effect

A. Distribution of detomidine (D) to B. α2 receptor saturation and finite number ofα 2 receptors (R) disposition of excess detomidine

Figure 1 – The schematic illustrates the theoretical plateau effect of detomidine whereby increasing the dose does not increase the physiologic response beyond a maximum effect, or plateau. View A – Detomidine dosage (D) exceeds the finite alpha α( )-2 receptor (R) capacity. View B – Alpha-2 receptor-bound detomidine (R+D) exerts a sedative effect. However, whenα 2 neuroreceptors become saturated, excess detomidine remains unbound and exerts little or no sedative or other physiologic effect. The result is a self-limiting, non- toxic response. After a physiologic plateau is reached, the sedative effect is prolonged (but not increased) when excess detomidine binds to α2 receptors as they become available until drug metabolism is complete. 5 Table 1 – Case profile and dosages in the Dormosedan (detomidine) 5-year Ohio State University clinical trial (2003-2008)

Ave. dose size* (mL) for Standing procedures Number 1,100-lb horse & route

Floating, motorized (by temperament) Quiet (n = 502) 573 1.2 (0.5-1.8) IV Excited, controllable (n = 56) 1.5 (1-2.25) IV Agitated, fractious (n = 15) 2.5 (2-3) IM Joint injection 268 0.75 (0.5-1.8) IV Laceration repair 161 1.2 (1-2.5 mL) IV Other 514 Total standing procedures 1,516 *Volume based on recommended dosage of 20 or 40 mcg/kg (1 or 2 mL per 1,100 lbs). occurs. If the horse is fractious or agitated, IM Interestingly, when I use a full dose of administration is generally more convenient. detomidine on a stand-alone basis, my When detomidine is given by the slower- cost is less than $5 more than the cost of a acting IM route, the clinician should wait combination of 1.5 mL of xylazine, one-third at least 15 minutes before proceeding. An the full dose of detomidine, and 1 mL of alternative approach for a difficult- to-manage butorphanol. I find that this small increase in horse is to give a partial IM dose followed by cost versus a commonly used combination IV administration of the remainder of the full protocol can be readily justified and passed dose. Using both routes of administration also on to the client. Keep in mind that detomidine results in a more rapid effect from the IV dose is not the only premium priced product used and a more sustained effect from the IM dose. in equine medicine. Hyaluronate and certain I always administer the injection in the neck, antibiotics, for example, are also costly which places me in the safest position relative but make valuable contributions to clinical to the horse. practice. Pricing for profit Clinical perspective Pricing to the client is an important aspect No procedure is more essential to equine of using detomidine because it is much practice than safe, effective, and reliable more expensive than generically available sedation. An obsolete concept in equine (and less efficacious) xylazine. Clinicians medicine, largely sustained by tradition and frequently claim that detomidine is “too misinformation, is a reliance on multi-modal expensive”. However, I believe price should sedation-analgesia protocols for standing be determined by value. Detomidine is an procedures when sole use of detomidine exceptional drug for its intended use, virtually represents a superior alternative. The ensuring safe sedation. The added cost can performance advantages of detomidine be legitimately passed on to the client and include: justified as the price for optimum safety of • Greater efficiency in administration the veterinarian and the animal and improved compared to multi-modal protocols. case management. Price schedules will vary by practice, of course, but I charge the cost • Minimizing the need for intra-operative of the volume of product used plus 50% plus redosing. a $20 administration fee. This assures a profit • Greater consistency of effect than partial- for the procedure by combining a flat-fee for dose combination protocols. the service with an incremental fee based on • Avoidance of side effects associated with the amount of product used. opioids (ataxia, head pressing). 6 • Reversibility when appropriate. 4. Daunt D. Detomidine in equine • Significant analgesia in addition to sedation and analgesia. Comp Cont Edu sedation. 1995;17:1405-1411. • Greater duration and depth of sedation 5. Jochle W, Baker GJ, Brown, J, et al. and analgesia versus xylazine or Comparison of detomidine, butorphanol, romifidine flunixin meglumine and xylazine in clinical cases of equine colic. Equine Vet J Suppl • Flexible route of administration. 1989;7:111-116. • Variable dosage size depending on the animal’s temperament and depth and 6. Hamm D, Turchi P, Jochle W. Sedative duration of effect desired. and analgesic effects of detomidine and romifidine in horses. Vet Rec 1995;136:324- • Eliminating the need for special handling 327. required for a scheduled drug. 7. Sellon DC, Monroe VL, Roberts MC, et al. The exceptional potency of detomidine Pharmacokinetics and adverse effects is the source of its consistent treatment of butorphanol administered by single effect. However, the profound sedation intravenous injection or continuous and cardiorespiratory effects induced by intravenous infusion in horses. Am J Vet detomidine have inspired an overabundance Res 2001;62:183-189. of caution in its use, particularly in the form of advocacy for partial doses. This hesitancy 8. Kamerling SG, Cravens WMT, Bagwell is not supported by the pharmacology of CA. Objective assessment of detomidine- detomidine where a self-limiting plateau induced analgesia and sedation in the effect prevents adverse physiologic effects. horse. Eur J Pharmacol 1988;151:1-8. Dose-tolerance studies of detomidine given 9. Owens JG, Kamerling SG, Stanton SR, repeatedly at multiple-dose levels provide et al. Evaluation of detomidine-induced assurance of product safety when used as analgesia in horses with chronic hoof pain. recommended. In a 5-year clinical trial of J Pharmacol Exp Ther 1996;278:179-184. at the Ohio State University equine clinic, we have yet to experience an adverse case 10. Detomidine Freedom of Information outcome associated with detomidine, even Summary, NADA 140-862, December, when it is given at dosages greater than label 1989. guidelines. 11. Sarazan RD, Starke WA, Krause GF, et al. Cadiovascular effects of detomidine, Acknowledgement a new alpha-2 adrenoceptor agonist, in The author thanks Mark Dana of Scientific the conscious pony. J Vet Pharmacol Ther Communications Services for assistance in 1989;12:378-388. preparing this report. 12. Hubbell JAE. Chemical restraint for References standing procedures in the horse. Proc North Am Vet Conf 2006;20:113-115. 1. Chambers JP, Livingston A, Waterman AE, et al. Analgesic effects of detomidine in 13. Grubb TL, Muir WW 3rd, Bertone AL, et thoroughbred horses with chronic tendon al. Use of yohimbine to reverse prolonged injury. Res Vet Sci 1993;54:52-56. effects of xylazine hydrochloride in a horse being treated with chloramphenicol. 2. Moens Y, Lanz F, Doherr MG, et al. A J Am Vet Med Assoc 1997;210:1771-1773. comparison of the antinociceptive effects of xylazine, detomidine and romifidine on 14. Hubbell JA, Muir WW. Antagonism of experimental pain in horses. Vet Anaesth detomidine sedation in the horse using Analg 2003;30:183-190. intravenous tolazoline or atipamezole. Equine Vet J 2006;38:238-241. 3. Virtanen R. Pharmacological profiles of medetomidine and its antagonist, atipamezole. Acta Vet Scand Suppl 1989;85:29-37. 7 All trademarks are the property of Zoetis Services LLC or a related company or a licensor unless otherwise noted. ©2018 Zoetis Inc. All rights reserved. DOR-00043 8