Chapter 18: Drugs for the Control of Pain

Acute or Chronic Pain

Types of pain: Nociceptor pain: Caused by injury to tissue. Usually will respond to conventional pain relief mechanisms. Somatic pain: Sharp, localized sensations in the body. Visceral pain: Generalized dull and internal throbbing or aching.  Neuropathic pain: Pain caused by direct injury to the nerve.  Hard to treat. Complementary and alternative treatments: These can help improve patient's mood, reduce anxiety,and provide patient with a sense of control. They often relax the muscles, strengthen coping abilities, and improve quality of life.  Intractable pain: Pain that isn't easy to relieve.  Co-analgesics may be used for this.  Adjuvant analgesics: Drugs not typically classified as analgesics, but can provide relief for specific types of pain. Examples include carbamazepine (Tegretol) for trigeminal neuralgia;  valproic aicid (Depakene) for migraine pain; gabapentin (Neuronin) for postheretic neuralgia; and pregabalin (Lyrica) for fibromyalgia, postherpetic neuralgia, and peripheral diabetic neuropathy. Anesthetic nerve blocking drugs are also used. Lidoderm is used to reduce pain and discomfort caused by skin irritations, and corticosteroids can be used for inflammatory pain.  Meds are also used off label. Amitriptylline (Elavil), nortriptyline (Aventyl, Pamelor) and imipramine (Tofranil) are all used or chronic and neuropathic pain. Mexiletine (Mexitil) and flecainide (Tambocor) can help neuropathic pain. Neural mechanisms for pain: A neurotransmitter called substance P is thought to be responsible for continuing the pain message up the spinal cord.  Substance P is affected by things like endogenous opioids (endorphins, dysnorphins, and enkephalins).  Opioids act within the CNS, whereas NSAIDs act at the nociceptor level.

Opioid analgesics for severe pain

Classification: Opium is a milky extract from the unripe seeds of the poppy plant.  Substances derived from opium are called opiates.  Opioid is a general term for both natural and synthetic drugs that have opiate-like activity.  Opioids interact with the mu, kappa, delta, and nociceptin receptors.  The mu and kappa receptors are the one traditionally targeted. Delta receptors are connected with the emotional and affective components of pain.  B/c there's multiple sites for interaction, there are 3 general types of drug-receptor interactions: Opioid agonist: Mu and kappa are activated. Morphine and codeine are examples.  Opioid antagonists: Both mu and kappa are blocked. Naxolone is an example. Mixed opioid agonist-antagonists: Occupies one receptor and block or don't affect the other. 

Opioid Agonists

Pharmacotherapy: Single to multiple doses of PO and IV administered opioids can alleviate severe pain w/o producing respiratory depression.  Opioids also suppress cough reflex, slow motility of GI tract, cause sedation,  cause euphoria, and cause intense relaxation. They can also, however, cause nausea, vomiting, constipation, and respiratory depression.  All opioids have the potential to cause physical and physiological dependence. Over the years, providers have hesitated to administer the proper amount b/c of this. But when used according to accepted medical practice, patients can get pain relief without fear of addiction or adverse effects.  It is common practice to combine opioids and nonnarcotic analgesics. The 2 classes work synergistically to relieve pain.  Additional doses of a combo product should not be used unless the dose of nonnarcotic analgesics does not exceed recommended dose.  This is because combination products may raise the dose of both drugs to unacceptable levels.  Some opioids are used primarily for conditions other than pain relief. Alfentanil (Alfenta), remifentanil (Ultiva), and sufentanil (Sufenta) are used to provide continuous pain relief during or after surgery and during induction and maintenance of general anesthesia. Codeine is prescribed as a cough suppressant.  Fentanyl is given as a patch, nasal spray, and as a lozenge.  These drugs should only be used for chronic cancer pain or in the management of acute or post-op pain, 

Opioid Antagonists

Background information: Any opioid can be abused for psychoactive effects, although the most abused ones are morphene, meperidine, oxycodone, and heroin are preferred because of their potency. Once injected, heroin rapidly crosses the blood-brain barrier to enter the brain, where it is metabolized to morphine.  The initial euphoria is the rush. Several hours of deep relaxation ensue.  Pharmacotherapy: Opioid antagonists are often used to reverse severe symptoms of opioid intoxication, such as sedation or respiratory disress.  If we don't know what's causing the problem, we can use these drugs to diagnose it as an opioid overdose.  Naloxone (Evzio and Narcan) may be used to revere respiratory depression and other acute symptoms.  Antagonists will also be used with opioids for patients with respiratory ailments. Naltrexone mixed with morphine (Embeda) is used for moderate to severe pain control when continuous, around the clock analgesic is needed extensively, Targiniq ER, which is oxycodone and naloxone, can also be used. 

Mixed agonist-antagonists

Provide analgesia, but the withdraw symptoms or adverse effects are not as intense due to partial activity.  Treatment for opioid dependence:  Opioids have a greater risk for dependence than almost any other class of meds. Tolerance to euphoric effects develops relatively quickly, causing dose elevation and more frequent dosing, which causes physical dependence faster. People hooked on opioids will experience withdraw symptoms for about a week if they stop abruptly. They may experience cravings for months or even years after discontinuation.  One way to treat dependence have been to give patients methadone (Dolophine). Methadone is an opioid, but doesn't cause the same degree of euphoria.  Does not cure dependence. The patients must continue methadone maintenance therapy for months or years until the patient decides to enter a total withdrawal program.  A newer treatment is to administer buprenorphine (Buprenex, Butrans, Suboxone, and Zubsolv), which contains both buprenorphine and naloxone. The naloxone would cause unpleasant withdrawal symptoms if the drug is abused, so drug is less likely to be abused.  Bunavail, Suboxone, and Zubsolve treatment can be used. These do not require daily reporting to a clinic, unlike methadone.  Naloxone injector (Evzio) combined with buprenorphine or pentazocine may result in incomplete reversal of respiratory depression in patients with respiratory conditions.  B/c large doses of naloxone is needed to antagonize thee drugs.  There may be a tendency to overprescribe mixed opioids, which promotes drug misuse. 

Nonopioid analgesics

NSAIDs Inhibits pain mediators at the nociceptor level.  Specifically, they inhibit cyclooxygenase (COX), which is an enzyme responsible for the formation of prostaglandins. When inhibited, inflammation and pain are reduced.  These drugs have antipyretic and anti-inflammatory agents, giving them an advantage over opioids.  Aspirin, Ibuprofin, and COX-2 Inhibitors: Aspirin and ibuprofen are safe and well tolerated by most patients when used at low-moderate doses.  Differences: Aspirin has greater effect on blood coagulation and poses a higher risk for GI bleeding than ibuprofin does.  After tissue is damaged, prostaglandins are formed with help of COX-1 and COX-2. Aspirin and ibuprofin inhibit both.  COX inhibition is basis of NSAID therapy.  COX-2  enzyme is more specific for synthesis of inflammatory prostaglandins, so drugs that selectively inhibit that provide more specific and peripheral pain relief. Celecoxib (Celebrex) is an example of one of these.  Centrally Acting Drugs: Exert effects directly within the brain and spinal cord. It bypasses the nociceptor level.  Acetaminophen is an example of a centrally acting nonopioid analgesic. It reduces fever by acting on the hypothalamus and causing dilation of peripheral blood vessels. Does not produce GI bleeding or ulcers and does not exhibit cardiotoxicity. Excellent safety profile when given in proper doses, but hepatotoxicity can occur when used too much. Tramadol (Ultram) and ziconotide (Prialt) are more centrally acting drugs. Tramadol is more widely prescribed.  Tramadol has a weak opioid effect. It inhibits reuptake of norepinephrine and serotonin in spinal neurons. It's well tolerated, but can cause headache, nausea, vomiting, constipation, and lethargy. 

Tension headaches and migraines

Headache classification: Most common type is the tension headache. It happens when muscles of the head and neck become very tight b/c of stress. They are self limiting, and generally just considered an annoyance.  Migraine is the most painful type of headache. It's characterized by throbbing or pulsating pain, which is occasionally preceeded by an aura. Drug therapy: Tension headaches can usually be treated with OTC analgesics. If they get worse, however, the alternatives are things like Ascomp, Fioricet, Phrenilin, and Phrenilin Forte.  2 major drug classes are used as antimigraine drugs: triptans and ergot alkaloids. Both are serotinin agonists.  In addition, some popular serotonin agonists that act as antianxiety drugs may be used, These include fluoxetine (Prozac) and buspirone (BuSpar).  Pharmacotherapy for migraines begin with acetaminophen and NSAIDs, then moves on to the triptans. The triptans are selective for the 5-HT1-receptor subtype, and are thought to act by constricting intracranial vessels. If patients are not responsive to triptans, the ergot alkaloids may be used. The first drug was ergotamine (Ergostat). Modifications of this drug includes dihydroergoamine mesylate (D.H.E. 45, Migranal). Ergot alkaloids interact with adrenergic and serotonergic receptors, so they produce multiple actions and side effects. Many are pregnancy category X. Prophylactic drugs include things like antiseizure drugs, beta-adrenergic blockers, calcium channel blockers, antidepressants, and neruromuscular blockers. Because of the side effect potential, prophylaxis is initiated only if the incidence for migraines is high and unresponsive to abortive drugs. These drugs include propanolol (Inderal), Amitriptyline (Elavil), and onabotulinumtoxin A (Botox). Botox inhibits neuromuscular transmission by blocking the release of acetylcholine from axon terminals innervating skeletal muscle.