Analgesic drugs and sedatives (Proceedings)

Pain management in veterinary medicine was practically unheard of twenty years ago, and it has advanced dramatically over the past decade. Not only is the physiology of pain and its effects becoming better understood, pain management is considered a vital part of most treatment plans. The approach towards pain has changed from questioning whether animals feel pain to widespread acceptance that not only do animals feel pain, but pain will inhibit recovery and cause undue suffering.

The International Veterinary Academy of Pain Management (www.IVAPM.org) was formed in 2003 to promote and advance pain management, and currently has a credentialing process in it. All veterinary personnel can benefit from knowledge of analgesics and understanding approaches to this topic.

It is important to recognize that analgesics cannot be treated as a "one size fits all" approach to pain management for every drug will affect every animal differently. Since the goal is to maximize a drug's benefits while minimizing side effects, it is common to use a multi-modal approach to pain management. Multi-modal pain management uses combinations of drugs to calm the patient and keep them pain free. There is a synergistic effect by using combinations of drugs meaning the drugs are more effective at lower doses, thus limiting their side effects.

Understanding the physiology of pain allows one to treat it more effectively. A simple definition of pain is it is an electrical impulse that travels from a nerve ending, via a nerve tract, and is perceived in the brain. Free nerve endings called nociceptors are the pain receptors, and there are different types of receptors that respond to different types of pain. The receptors associated with opioids are mu, kappa, and sigma. Mu and kappa receptors are responsible for sedation, analgesia, and respiratory depression, while sigma receptors are involved with opioid side effects such as dysphoria and hallucinations. The drug's duration of action must be considered because nociceptors can continue to send pain signals even after the stimuli stops and can cause ongoing discomfort or tissue damage. Repeated doses are sometimes needed.

Opioids

Opioids are very effective analgesic drugs so they are used most often. There are three categories:

     • Pure agonists stimulate the entire receptor. They are the most potent and effective with acute, traumatic, and intense pain. These drugs provide the most analgesia while the side effects such as hypotension, respiratory depression, hypothermia, vomiting, and ileus are more likely and possibly more profound. These drugs include Morphine (0.5-2 mg/kg in dogs and 0.1-0.3 mg/kg in cats), Hydromorphone (0.05-0.2 mg/kg), Oxymorphone (0.05-0.2 mg/kg), and Fentanyl. Fentanyl's duration is very short so it must be administered intravenously as a continuous rate infusion (CRI) to maintain analgesia. There are also Fentanyl transdermal patches, which are applied to the skin and provide continuous pain relief for up to 72 hours, but absorption, efficacy, and duration can vary greatly depending on proper placement and the animal.

     • Partial agonists stimulate only part of the receptor. These drugs provide less analgesia, and the side effects are the same as pure agonists, but with less intensity. They are commonly used in routine procedures such as a minor laceration or abscess repair, and castrations. Drugs include Buprenorphine (0.01-0.02 mg/kg), and Butorphanol (0.1-0.4 mg/kg). Buprenorphine also can be given sublingually to cats making it a good medication for continuing pain relief at home. A synthetic opioid such as Tramadol (2-4 mg/kg up to QID), an oral tablet, is also a good medication to send home with owners. Butorphanol's analgesic effects are limited, but it is a good sedative. It is often used in conjunction with other medications to provide sedation and analgesia

It should be noted that partial agonists should not be used with pure agonists because they counteract each other's effects. Each one is trying to stimulate the receptor, and they end up "pushing" one another off.

Partial agonists also have a "ceiling effect" with regards to cardiovascular effects, while pure agonists do not. Overdosing pure agonists can cause respiratory or cardiovascular arrest, while this is not likely with an overdose of a partial agonist.

     • Antagonists block the receptors and are used to reverse opioid effects if the patient is not responding well. The most common antagonist is Naloxone (0.002-0.2 mg/kg for a duration of one hour).

It should also be noted that opioid administration can induce an excitability phase before taking its full effect, but adding tranquilizers minimizes the possibility. Often low doses of tranquilizers are beneficial to minimize the effect of stress. Sleeping is a healing process, and recovery is inhibited for hospitalized patients that lack rest or sleep.

Tranquilizers

Tranquilizers calm patients, but provide no analgesia. There are two derivatives commonly used in veterinary medicine:

     • Phenothiazine tranquilizers such as Acepromazine (0.025-0.2 mg/kg-max dose 3mg) are effective, but there are side effects to be considered. Acepromazine can cause splenic enlargement and/or hypotension, so avoid use with splenomegaly or splenic rupture, and either use a very low dose or avoid with compromised patients. It was considered to reduce the seizure threshold for a long time, and even though current literature disputes this, some veterinarians still choose to avoid its use in epileptic patients.

     • Benzodiazepine tranquilizers such as Diazepam (0.2-0.6 mg/kg) or Midazolam (0.1-0.2 mg/kg) calm patients. Diazepam is also commonly used as an anticonvulsant and immediate treatment for status epilepticus.

Alpha-2 agonists

There has been an increase the use of in Alpha-2 Agonists such as (Dex)medetomidine as the understanding of their mechanism and benefits has grown, and misconceptions have been dismissed. These drugs provide profound sedation, mild to moderate analgesia, muscle relaxation, and relieves anxiety (anxiolysis). It is reversible with administering an equal volume of Atipamazole IM. (Dex)medetomidine can be used in a variety of ways including microdoses (1-3 mcg/kg), or administered as a CRI (1-3 mcg/kg/hr) to provide sedation. It can also be used in conjunction with a variety of drugs including Butorphanol, Buprenorphine, and Hydromorphone to provide anesthesia for minor procedures.

Side effects include peripheral vasoconstriction, increased vagal tone, increased chance of atrioventricular (AV) block, bradycardia, and respiratory depression. Peripheral vasoconstriction can cause the mucous membranes to appear pale, and the subsequent temporary hypertension can cause bradycardia as a compensatory response. Administering anticholinergics such as Atropine is contraindicated because they will increase pressure on the heart, therefore increasing oxygen consumption and the chance of arrhythmias and complications. Blood pressure monitoring can demonstrate the effects the drug is having on the animal, and partial or total reversal with Atipamazole is indicated if there are adverse effects. Alpha-2 agonists should be avoided in compromised patients.

NSAIDs

Non-steroidal anti-inflammatories (NSAIDs) are effective in treating acute and chronic pain, and they have a synergistic effect when used with opioids. There are many different drugs available in oral form, and injectables include Meloxicam and Carprofen, but all NSAIDS should be used with caution. It is essential to know your patient before giving them. Side effects can include gastrointestinal irritation/ulcers, impaired platelet function, and platelet aggregation which can increase the chance of intraoperative bleeding. A complete blood count (CBC) and biochemical profile should be performed prior to using NSAIDs because they are filtered through the kidneys and metabolized through the liver. They should not be used if the patient is on steroids or is starting steroids within 7 days, is dehydrated, hypotensive, hypovolemic, or has impaired gastrointestinal, clotting, kidney, or liver function. NSAIDs should be discontinued if the patient has any signs of GI bleeding (melena, hematochezia), starts vomiting, has diarrhea, or becomes inappetant.

Adjunct medications

Gabapentin (10-30 mg/kg) is an anticonvulsant that at lower doses works well as an adjunct analgesic medication and can be used with opioids or NSAIDs to decrease neurogenic pain (pain originating in the nervous system such as intervertebral disc disease or lumbosacral disease) with minimal side effects.

NMDA (N-methyl-D-aspartate) receptor antagonists such as Ketamine (2-4 mg/kg) or Amantadine (1.25-4 mg/kg) reduce stimulation of nociceptors in the spinal cord. This is helpful in reducing wind-up (defined in Premedication section) and, though they are effective as adjuncts with other types of analgesics, NMDA antagonists do not solely provide adequate analgesia. Ketamine, a dissociative anesthetic that produces a cataleptic state, can be used in conjunction with a variety of medications, but avoid its use in patients with head trauma, epilepsy, and heart disease.

Commonly used drug combinations

Effective sedation/analgesia drug combinations cause neuroleptanalgesia, which is calmness and analgesia induced by a drug combination. As stated earlier, each patient will react differently so combinations can be mixed and dosed specific to the patient and condition. Some combinations include:

      a. Acepromazine/Butorphanol, or Acepromazine/Buprenorphine if more analgesia is needed.

      b. Butorphanol/Diazepam IV (these must be administered separately as they precipitate)

      c. (Dex)medetomidine/Butorphanol OR Hydromorphone OR Buprenorphine

      d. "Kitty magic" Ketamine/(Dex)medetomidine/Butorphanol 0.1 ml of each IM

      e. Ketamine/Diazepam

      f. B-, M-, or HAG, which is Butorphanol, Morphine, or Hydromorphone combined with Acepromazine and Glycopyrrolate is a common premedication.

Premedication

Premedicating patients before anesthetic induction is a common accepted standard of care. The benefits far outweigh the risks as stress can cause an epinephrine release that can cause arrhythmias under anesthesia. It also reduces wind up for the premedicated patient is a calmer patient that is provided a smooth induction with perioperative pain relief that decreases the amount of induction and inhalant anesthesia used. The benefits of decreasing these are discussed further in the CRI section of this series.

Wind-up is a term used for when the patient is in so much pain that it is difficult to get the pain and anxiety under control. It usually requires more drugs with subsequent side effects to "catch up". It is because of this that analgesics are administered on a schedule rather than when the patient appears to be in pain. The patient's vital signs should still be monitored to ensure they are not overwhelmed from the drug's side effects.

Anticholinergics such as Atropine and Glycopyrrolate are often added to preanesthetic combinations. These drugs do not have a sedative nor analgesic effect, but they block the effects of the neurotransmitter acetylcholine. Acetylcholine is involved with glands and involuntary muscles, so anticholinergic drugs can cause decreased salivary secretions and gastric motility. They also increase the heart rate so contraindications include tachycardia and a history of heart disease. Constipation can also be seen. Some doctors prefer to limit their use of anticholinergics as a treatment rather than a preventative for bradycardia or excessive ptalyism.

References

McKelvey, Diane, Hollingshead, Wayne. Veterinary Anesthesia and Analgesia, Third Edition. Mosby. 2003.

Paddleford, Robert. Manual of Small Animal Anesthesia. W.B. Saunders Company. 1999.

Plumb, Donald. Veterinary Drug Handbook. Fifth Edition. Wiley-Blackwell. 2005.