Perioperative Use of Nonsteroidal Anti-Inflammatory Analgesics

Karol Mathews Canada

INTRODUCTION

Several non-steroidal anti-inflammatory analgesics (NSAIAs) have been employed to successfully control post-operative pain in dogs and cats. As the safety of NSAIAs is of major concern, assessment of potential adverse affects must be included in the overall evaluation.

One mode of action of NSAIAs in conferring analgesia is through reduction in prostaglandin (PG) synthesis via inhibition of cyclooxygenase (COX)-1 (homeostatic or constitutive) or COX-2 (inflammatory or inducible) isoenzymes, or both. Under normal circumstances, PGs synthesized as a result of COX-1 activity, serve to maintain physiologic functions such as gastric mucosal integrity, modulation of renal blood flow, and platelet function. Following tissue injury, activation of the COX-2 isoform leads to the production of PGs which act as mediators of inflammation, causing hyperalgesia and pain. The differential inhibition of these two COX isoforms by NSAIAs is thought to result in not only the excellent anti-inflammatory and analgesic benefits of these agents, but in the potential for adverse effects under certain conditions. Thus, the development of NSAIAs that preferentially inhibit COX-2 over COX-1, may provide safer analgesics. However, current use of these agents in humans indicates that this may not always be the case.

At the Ontario Veterinary College (OVC), University of Guelph, currently available NSAIAs have displayed analgesic efficacy comparable to opioids such as oxymorphone and morphine, and superior to butorphanol, with duration of action of approximately 12 to 20 hours. These findings are supported by other reports. In addition to controlling post-surgical pain, NSAIAs are extremely effective in controlling inflammatory pain associated with traumatic soft tissue injury and orthopedic cancer pain.

INDICATIONS

Post-operative, especially orthopedic, pain in the well- hydrated, normotensive, young-to middle-aged dog or cat with normal renal function, without hemostatic abnormalities, without evidence or concern for gastric ulceration and not receiving corticosteroids or aspirin (see contraindications below). My experience has been with animals receiving intra-operative IV fluids. Geriatric animals in otherwise good health and with normal renal and hepatic function may be considered on an individual basis as suitable candidates for NSAIA administration. Carprofen, meloxicam or ketoprofen can be co-administered with opioids. An opioid should be administered with the NSAIA initially to ensure adequate analgesia until the NSAIA is effective, approximately 45 to 60 minutes after administration. Carprofen (dogs) or meloxicam (dogs and cats) can be administered pre-operatively, as demonstrated by previous clinical use in healthy animals with normal renal function. There is evidence that glomerular filtration rate may be altered with selective NSAIAs if intra-operative fluids are not administered.

Currently, fluids are administered throughout anesthesia at our institution. Gastric mucosal erosion/ulceration may also be a concern with NSAIA use; however, these lesions may also be present without the use of NSAIAs when animals are stressed. NSAIAs are especially effective for surgical pain where inflammation is a component e.g., bone tumours (especially after biopsy), mastectomy, cystotomy, or injury (degloving) (Mathews, unpublished observations). As these patients may be more sensitive to NSAIA toxicity, a lower dose may be advised. Ketoprofen may be used for up to five days with re-evaluation at that time but should not be used pre-operatively. The side effects of NSAIAs may occur in any patient, therefore, the patient should be monitored for blood in the feces or melena, vomiting, and increased water consumption. Other indications for the use of NSAIAs are most orthopedic procedures, including amputation, ophthalmological procedures where anti-inflammatory therapy is required, and dental procedures. Where bleeding is, or may be, of concern, carprofen or meloxicam may have minimal to no effect on coagulation due to lack of anti-thromboxane activity. Ketoprofen should not be used in these cases due to potential for anti-thromboxane activity.

RELATIVE CONTRAINDICATIONS FOR USE OF NON-STEROIDAL ANTI-INFLAMMATORY ANALGESICS

While it is generally recommended that the use of NSAIAs should be avoided in the geriatric patient, there is no contradiction to their use providing renal and hepatic functions are normal. NSAIAs have been used in our clinic at the lower dose when opioids do not control post-operative pain. These patients had a creatinine level less than 130 umol/L, were well-hydrated and receiving IV fluids, and did not have evidence of gastric ulcer (vomiting, melena, etc.), or other contraindications (see below). Sucralfate, preferably the suspension 2.5�5 mL, (small to large dog) or misoprostal 2�5 mcg/kg every eight hours, should be administered to these patients if they have been traumatized or are unduly stressed. If the use of NSAIAs (see contraindications) is being considered after a traumatic incident (where surgical intervention is not planned for 48 hours), the patient should be stable without any evidence of hemorrhage (it may take several hours to determine this) and should be maintained on IV crystalloid therapy until adequate fluid intake has been guaranteed. Opioids may be required in the interim. Note: carprofen has been approved for pre-operative use in Europe.�

ABSOLUTE CONTRAINDICATIONS FOR USE OF NSAIAS

Non-steroidal anti-inflammatory analgesics should not be administered to patients with renal insufficiency (creatinine > the median for your laboratory after rehydration); dehydration; hypotension; conditions associated with low �effective circulating volume� (e.g., congestive heart failure, ascites, diuretics); thrombocytopenia; von Willebrand�s disease; concurrent use of other NSAIAs (e.g., aspirin) or corticosteroids; evidence of gastric ulceration or gastrointestinal disorder of any kind; liver disease; intervertebral disc disease where surgical intervention is being considered or where medical management with corticosteroids is, or will be, required; shock or trauma cases upon presentation; or hemorrhage (e.g., epistaxis, hemangiosarcoma, head trauma). Patients with severe or poorly controlled asthma or other moderate to severe pulmonary disease may deteriorate with NSAIA use. However, specific indications should be based on manufacturer�s recommendations and appropriate clinical trials. The median value for creatinine is given as the recommended upper limit when considering NSAIA use as the upper limit of normal can indicate a two-third reduction in renal function. As each NSAIA has variable effects on renal function, and where analgesia may be necessary in the patient with a creatinine above the median but within normal range, the benefit may outweigh the risk. In this instance, it is recommended that only a single dose is administered and the patient is supported with IV fluids. Potential NSAIA induced renal insufficiency is usually temporary and reversible with administration of IV fluids.

The safety of the different NSAIAs may be better elucidated with future use of these analgesics in veterinary patients of various ages and with a range of painful problems. Until such reports appear in the scientific literature, careful monitoring of possible side effects should be conducted. Dosing should be based on lean weight of the animal.

DOSAGES

Carprofen���

Dogs 4.0 mg/kg upon induction, 2.2 mg/kg q24h IV, SC, PO. Or 2.2 mg/kg q12h if required. Cats 4.0mg/kg SC once (Europe).

Ketoprofen

Dogs 2.0 mg/kg IV, SC, IM, Cats 2.0 mg/kg SC once. Repeat 1.0 mg/kg/24h x five days then reassess with reduction of dosing for prolonged use

Meloxicam

Dogs 0.2 mg/kg IV, SC, PO to start, then 0.1 mg/kg q 24h. Although not yet approved in cats, studies using 0.2 mg/kg (a lower dose is advised for < moderate to severe pain) followed by 0.1 mg/kg q 24h for 2-3 days has proved to be efficacious and safe however, the therapeutic index is narrow.

Tolfenamic Acid

Dogs 4 mg/kg PO, SC once daily for three days and off for four days. Repeat.

Etodolac

Dogs 10�15 mg/kg PO q24h

Due to the variable dosing from country to country, it is advised that the label instructions be followed where possible. Lowering the dose of NSAIA is always recommended when dosing to effect. Never increase above the recommendations. As with opioids, a sliding scale approach should be used when administering NSAIAs. Less than the recommended dosages can be used when the level of pain warrants this. For example, the dose of an NSAIA required after a fracture repair will be higher than that after a more minor procedure. By using as low a dose as possible, you will reduce potential side effects associated with some of these drugs, yet analgesia will still be good to excellent. Even alternate day therapy may be appropriate. When using combination opioids and NSAIAs, again a lower dose of either drug may be appropriate depending on the degree of pain.

REFERENCES

1.  Davidson G, Etodolac. Comp Con Educ Pract Vet. 1999;21(6):494-495

2.  Lascelles BDX, Cripps P, Mirchandani S, Waterman AE. Carprofen as an analgesic for postoperative pain in cats: Dose titration and assessment of efficacy in comparison to pethidine hydrochloride. Journal of small Animal Practice 1995; 36:535-541

3.  Lascelles BDX, Butterworth SJ, Waterman AE,. Postoperative analgesic and sedative effects of carprofen and pethidine in dogs. Veterinary Record.1994; 134; 187-191

4.  Slingsby LS, Waterman-Pearson AE. Comparison of pethidine, buprenorphine and ketoprofen for post-operative analgesia after ovariohysterectomy in the cat. Veterinary Record 1998, 143; 185-189

5.  Lascelles BDX Analgesia in cats and the results of a field study examining the use of meloxicam in cats. Recent advances in non-steroidal anti-inflammatory therapy in small animals (Boehringer-Ingelheim)�Paris 1999. Proceedings pg 75

6.  Holger Schmidt. Efficacy and Safety of Metacam^® (meloxicam) in the control of peri-operative pain in the dog. Recent advances in non-steroidal anti-inflammatory therapy in small animals (Boehringer-Ingelheim)�Paris 1999. Proceedings pg 71

7.  Mathews KM, Pettifer G, R. Foster, McDonell W. a comparison of the safety and efficacy of meloxicam to ketoprofen and butorphanol for control of post-operative pain associated with soft tissue surgery in dogs. Recent advances in non-steroidal anti-inflammatory therapy in small animals (Boehringer-Ingelheim)�Paris 1999. Proceedings pg 67. Am J Vet Res 2001 (In Press)

8.  Mathews KM, Foster RA. A prospective study of the analgesic efficacy and potential side effects of ketoprofen in dogs after splenectomy (abstract). International Veterinary Emergency and Critical Care Symposium 1996 San Antonio, Texas. Proceedings pg 886

9.  Pibarot P, Dupuis J, Grisneaux E et al. Comparison of ketoprofen, oxymorphone hydrochloride and butorphanol in the treatment of postoperative pain in dogs. J Am Vet Med Assoc1997;211;438-444

10. Mathews KA, 1) Non-steroidal anti-inflammatory analgesics in pain management in dogs and cats II) Assessment of Pain Can Vet J 1996:37;539-545

11. Forsyth SF, Guilford WG, Pfeiffer DU. Effect of NSAID administration on creatinine clearance in healthy dogs undergoing anaesthesia and surgery. J Sm Anim Pract. 2000;41:547-550

12. Forsyth SF, Guilford WG, Haslett SJ, et al. Endoscopy of the gastroduodenal mucosa after carprofen, meloxicam and ketoprofen administration in dogs. J Small Anim Pract 39:421-424, 1998