Use of fentanyl as a patch and CRI (Proceedings)

Fentanyl is a schedule II narcotic approximately 100 times more potent than morphine. With IV administration, onset of the drug occurs rapidly, within 2 minutes, and is characterized by analgesia, sedation, and some ataxia. Duration of action for an IV bolus is short, 15-30 minutes, which makes short term IV administration appropriate for acute pain relief. Fentanyl works extremely well when combined with a low dose sedative (acepromazine) or anti-anxiety medication (midazolam) during short, painful procedures like biopsies, wound care, or radiographs on fractured limbs. However, fentanyl delivered as a continuous rate infusion (CRI) is a very cost effective and easily managed analgesic, and peak effects (therapeutic pain relief) are usually demonstrated within 30 minutes. At recommended dosages, fentanyl provides cardiovascular stability with minimal effects on cardiac output and no histamine release occurs that can lead to periods of hypotension. Fentanyl is metabolized in the liver and excreted by the kidneys. Vomiting rarely occurs although defecation may be stimulated due to relaxation of the anal sphincter.

A CRI of IV fentanyl is easily administered. The drug is compatible with most fluid solutions (check compatibility charts) and can be piggy backed into the fluid lines. It can be delivered straight from a syringe, using most available syringe pumps, or from a bag once the dosage and delivery have been calculated. Typical dosage of IV fentanyl is an initial bolus (loading dose) of 5μg/kg (cat) or 5-10μg/kg (dog) followed by a CRI of 2-4μg/kg/hr (cat) or 4-8μg/kg/hr (dog). Lower end dosages should be started on critically ill animals and titrated up if needed. Likewise, intra-operative dosages may start at the lower range, and will usually lower the concentration of inhalation anesthetic gas needed. The dosages may then be increased as needed upon recovery from general anesthesia. If an animal is showing unwanted behavior such as vocalization, restlessness, or thrashing a thorough assessment of the pet should be done. If the patient is cardiovascularly stable, it may be assumed the pet is still painful and the dosage of fentanyl CRI should be increased. It is my belief that the pain meds should not be removed from the patient under the assumption of dysphoria until a trial is performed to determine if more medication alleviates the behavior. If the patient is stable, a low dose sedative or anti-anxiety medication may also be warranted. If the pet continues to show negative side effects the drug can then be partially or completely reversed as instructed below.

Side effects of fentanyl are heavily dose dependant. Respiratory effects range from panting to infrequent apnea or hypoventilation. With clinical dosages, fentanyl has little effect on cardiac output or blood pressure and it equilibrates rapidly into cerebral spinal fluid. But as dosage increases, or with geriatric patients, decreases can occur in blood pressure, intracranial pressure, cerebral blood flow, and cerebral perfusion pressure. With increased dosages, fentanyl can cause vagally mediated bradycardia, sinus bradycardia, or possibly 1st or 2nd degree atrioventricular block. Barbiturate anesthesia may exacerbate this bradycardia. Contraindications for transdermal fentanyl use include drug hypersensitivity, central hypoventilation, fever, head trauma or suspected increased intracranial pressure, liver dysfunction, or renal insufficiency. Conventional wisdom warns against opioid use with head trauma due to hypoventilation resulting in an increase of CO2 and increased intracranial pressure. However, fentanyl alone at appropriate dosages does not increase intracranial pressure, cerebral blood flow, or cerebral perfusion. Fever dramatically increases the release and absorption of transdermal fentanyl, and care should be taken to ensure the fentanyl patch is applied in an area protected from any supplemental heat source (circulating water blanket). Liver dysfunction and renal insufficiency delay redistribution and excretion of the drug.

Should adverse side effects occur a pure agonist drug such as naloxone would provide complete reversal. Naloxone is short acting and may require repeat injections if side effects persist. Naloxone is best administered IV as a mixture of 1ml per 9ml of NaCl to effect only. Alternatively, 20μg/kg can be diluted into 10ml NaCl and given slow IV to effect, or the same dosage can be split half IV and half IM. Ideally only partial reversal is given to remove any unwanted dysphoria affects but maintain slight sedation and analgesia. Pain medications that are agonist/antagonist or partial agonist could also be used for partial reversal of fentanyl. Examples of these drugs; butorphanol, buprenorphine, and nalbuphine, would compete for or block pain receptors (mu, kappa, or delta opiate receptors). Interference with absorption or varied degrees of fentanyl reversal would occur. Low dose butorphanol at .05 mg/kg IV or buprenorphine at 5μg/kg IV may reverse unwanted delirium or dysphoria but maintain analgesia.

The Duragesic® fentanyl transdermal patch (Manufacturer: Janssen Pharmaceutica, Titusville, NJ) is a self-contained, drug delivery system specifically designed for relief of chronic pain. The transdermal patch is a thin, square to rectangular shaped, transparent plastic unit. For ease of explanation, it can be discussed as a matter of layers. A reservoir containing a gelled formulation of fentanyl and alcohol is sandwiched between a controlled release, permeable, membrane and an adhesive backing. The transdermal patch is applied to closely shaven, clean skin. The patch will deliver a specific amount of drug at a controlled rate for 72 hours. Some reports indicate the drug reservoir contains enough fentanyl for up to 100 hours. It is through passive diffusion that the gelled formulation of fentanyl reaches systemic circulation. The fentanyl patch is not approved for veterinary use. The onset of action for the patch, specifically speaking of therapeutic blood levels, is 12 hours for cats and up to 24 hours for dogs. Some reports indicate as little as 4 hours for cats and 12 hours for dogs. During the period before blood levels reach a therapeutic range, other opioids should be administered to control pain. A fentanyl CRI, oxymorphone, hydromorphone, or morphine can be delivered for pain. Patch dosage:

• Cats and small dogs (<10 kg): 25μg/hr

• Dogs (10 – 20 kg): 50μg/hr

• Dogs (20 – 30 kg): 75μg/hr

• Dogs (>30 kg): 100μg/hr

Indications for fentanyl patch use include chronic, cancer related pain or long term pain (>48 hrs) that may be of acute origin. Trauma patients, especially those with multiple fractures, and spinal fracture patients experience acute but severe pain for an extended period of time. Patients recovering from complicated thoracotomy surgery, especially multiple rib resections as can occur with certain neoplasias, benefit from the sustained analgesia of a fentanyl patch. In cats, post-operative use (greater than 2 days) after removal of a fibrosarcoma or radical mastectomy provides anxiety relief with a constant state of pain relief. Additionally cats suffering from burns or severe urinary obstruction seem to be less anxious or difficult to manage with fentanyl patch use. It must be remembered that the fentanyl patch is not indicated for immediate post-operative pain. A patch may be applied at that time, but it would not be effective immediately. A fentanyl bolus followed by a CRI would provide immediate post-operative relief.

A fentanyl patch delivers a continuous, pain free, and sustained plane of analgesia. It helps avoid the peaks and valleys of pain control that may occur with medications that are administered intermittently. When used on an outpatient basis, several factors make patch use ideal for treatment of chronic pain. Examples would include; extended time between doses, ease of maintaining pain control, and smooth transitions between old and new patch without breakthrough pain. These advantages would help alleviate stress for owners, and make the limited time together with their pet more enjoyable. Another advantage of using a fentanyl patch is a decrease in frequency of recording scheduled drug use, ie: one dose per 3 days vs. 4-6 doses per 24 hours with other pain medications. With outpatient use, it must be assured that the fentanyl patch be returned to the clinic when finished, or if it should happen to fall off, to be disposed of properly. Manufacturer suggestion states the patch should be folded onto itself and be witnessed while it is flushed down the toilet.

Several factors must be considered before patch placement. The patch must be placed in an area where the pet cannot bite or scratch it off. The area of skin must be relatively free of movement and away from any wounds. Sites that work well include the dorsal lateral thorax, dorsal cervical area of the neck, and the region of the lumbar vertebrae (just anterior to epidural injection location). Complete contact with the skin must be assured for proper absorption, and it must be kept dry to maintain adhesion. When preparing the skin, be careful not to cause any abrasions. Remove any dirt and loose hair but do not scrub the skin. Date, time, and initial the patch allowing visibility of the concentration. Labeling the patch prior to placement avoids sloppy writing. Exam gloves can be worn when placing to avoid any contact with the drug. Warming the patch to body temperature for several minutes seems to help the adhesive stick. Remove the peel off strip to expose the drug reservoir. Place the patch and firmly press down for about two minutes. Ensure that the entire perimeter of the patch is in full contact with the skin. Skin staples can be placed in the edges of the patch avoiding any puncture into the drug reservoir. A small, self adhesive type, bandage can be placed over it; provided that the bandage is labeled correctly with fentanyl patch and concentration, date, time, and initials. When placing consecutive patches a new area of skin is used to avoid skin irritation. Placing a new patch at 72 hours should allow overlap time between residual effect and new patch effectiveness. During chronic use on an outpatient, advise the owners of unwanted deep sedation or break through pain that may occur between patches.

Disadvantages of using transdermal fentanyl include: possible inaccurate release or absorption of drug resulting in variable plasma levels of fentanyl. Variations could result in less than adequate pain control or adverse side effects with increased absorptions. Increased absorptions and increased patient sensitivity have been attributed to dysphoria. It is my belief that dysphoria may occur in the initial stages of patch or CRI use where a patient may feel pronounced sedative effect (detached, "out of control" feeling), but has not yet reached a state of effective analgesia. Should adverse effects occur, the patch can be removed and a reversal agent administered. The initial cost of the patch may also be a disadvantage for clients that could outweigh the ease of use. Local skin irritation may occur. Another concern for patch use is the possible exposure of clients to fentanyl. The pet should be kept separate from small children, and owners should be instructed on how to handle the patch if it should fall off.

References

Harvey, Perkowski, and Quandt, in Small Animal Critical Care Medicine Silverstein and Hopper. Saunders 2009 pg 701, 705, and 788.

Thurmon, Tranquilli, and Benson in Lumb and Jones Essentials of Small Animal Anesthesia and Analgesia 3ed. Williams and Wilkins 1996 pg.778, 190

Paddleford. Manual of Small Animal Anesthesia 2ed. Saunders 1999 pg.27, 242-244

Schultheiss PJ, Morse BC, Baker WH: Evaluation of a transdermal fentanyl system in the dog. Contemporary Topics 34: 75-81, 1995.

Papich MG Management of Acute Pain: Fentanyl Patches and More in IVECCS proceedings 1998 pg 386-390.