University of Nizwa College of Pharmacy and Nursing School of Pharmacy PHARMACOTHERAPY - I PHCY 310 Lecture -14 “Pain Management” Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy University of Nizwa

Course Outcome Upon completion of this lecture the students will be able to Define and classify types of pain, and its clinical signs and symptoms, Describe pathophysiology of pain, Individualize the treatment for patients with acute and chronic pain.

Definition Pain is an unpleasant, subjective sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.

PATHOPHYSIOLOGY NOCICEPTIVE PAIN Nociceptive (acute) pain is either somatic (arising from skin, bone, joint, muscle, or connective tissue) or visceral (arising from internal organs such as the large intestine or pancreas). Stimulation of free nerve endings known as nociceptors is the first step leading to the sensation of pain. The endogenous opiate system modulates pain consists of neurotransmitters (e.g., enkephalins, dynorphins, and β-endorphins) and receptors (e.g., µ, δ, κ) that are found in CNS. Endogenous opioids bind to opioid receptors and inhibit the transmission of pain impulses.

NEUROPATHIC PAIN Neuropathic (chronic) pain is continued by abnormal processing of sensory input by peripheral or central nervous system. The neuropathic pain syndromes that are often difficult to treat (e.g., low back pain, diabetic neuropathy, post herpetic neuralgia, cancer-related pain, spinal cord injury). SYMPTOMS Pain described as sharp, dull, burning, shock like, tingling, shooting, radiating, fluctuating in intensity, and varying in location. Nonspecific symptoms include anxiety, depression, fatigue, insomnia, anger, and fear. SIGNS Acute pain can cause hypertension, tachycardia, diaphoresis, mydriasis, and pallor, but these signs are not diagnostic.

ACUTE PAIN MANAGEMENT Nonopioid Agents These drugs (except acetaminophen) reduce prostaglandins produced by arachidonic acid cascade. Decrease the number of pain impulses received by CNS. Aspirin given concurrently with other NSAIDs more likely to cause gastrointestinal (GI) side effects. The salicylate salts cause fewer GI side effects than aspirin and do not inhibit platelet aggregation. Acetaminophen has analgesic and antipyretic activity but little anti-inflammatory action. It is highly hepatotoxic on overdose.

Keterolac is a potent analgesic with moderate anti-inflammatory activity. In post operative pain, Keterolac is as effective as Morphine, meperidine or pentozocine. Common ADRs are somnolence, nausea and dizziness. Piroxicam and meloxicams have extended half life and hence dosed once daily. They are useful for treating rheumatologic conditions, because its anti-inflammatory action continues beyond duration of analgesia and once-daily dosing enhances patient compliances.

Newer cyclooxygenase-2-selective NSAID-celecoxib have minimal GI ulceration or interfere with platelet functions hence better than traditional NSAIDs for osteoarthritis flares or rheumatoid arthritis. Potent inhibition of PGI2 (prostacyclin) by these drugs increases risk of cardiovascular events particularly myocardial infarction with long term use (rofecoxib withdrawn from US market). Opioid Agents With oral analgesics, the onset of action usually takes about 45 minutes, and peak effect usually is seen in about 1 to 2 hours. Administration of opioids directly into the CNS (epidural and intrathecal/subarachnoid routes) is becoming prominent for acute pain.

These methods require careful monitoring because of marked sedation, respiratory depression, pruritus, nausea, vomiting, urinary retention, and hypotension. Naloxone is used to reverse respiratory depression, but continual infusion may be required. The analgesic effects of single doses of epidural opioids are given below: Morphine, 1 to 6 mg (onset 30 minutes, duration 6 to 24 hours) Hydromorphone, 1 to 2 mg (onset 15 minutes, duration 6 to 16 hrs) Fentanyl, 0.025 to 0.1 mg (onset 5 minutes, duration 1 to 4 hours)

Morphine and Congeners Morphine is considered by many clinicians to be the first-line agent for moderate to severe pain. It can be given oral, parenteral, or rectal. Nausea and vomiting-more likely in ambulatory patients and with initial dose. Respiratory depression increases progressively as doses are increased. It often manifests as a decrease in respiratory rate, and the cough reflex is also depressed.

Morphine produces venous and arteriolar dilatation, which may result in orthostatic hypotension. Morphine can cause constipation, spasms of the sphincter of Oddi, urinary retention, and pruritus (secondary to histamine release). Meperidine is less potent and has a shorter duration of action than morphine. Fentanyl is a synthetic opioid structurally related to meperidine. It is often used in anesthesiology as an adjunct to general anesthesia.

Central Analgesic Tramadol, a centrally acting analgesic for moderate to moderately severe pain, binds to µ opiate receptors and weakly inhibits norepinephrine and serotonin reuptake. It cause less respiratory depression than morphine at recommended doses, tramadol has a side-effect profile similar to that of other opioid analgesics. It may also enhance the risk of seizures. It may be useful for treating chronic pain, especially that of neuropathic origin, but it has little advantage over other opioid analgesics for acute pain.

CHRONIC PAIN MANAGEMENT NSAIDs are especially effective for bone pain. For cancer pain, round-the-clock schedules in conjunction with as-needed doses are employed when patients experience breakthrough pain. Methadone is best in treating cancer pain. The choice of opioid is controversial, but many clinicians prefer morphine for chronic cancer pain. The fentanyl patch may provide a more convenient dosing alternative in patients on stable regimens. Tricyclic antidepressants and anticonvulsants (e.g., gabapentin) can be effective for neuropathic pain.