Unit 3
Divalproex sodium (Depakote) or valproic acid Depakote is an anti-seizure medication that is also used in migraine prophylaxis It is effective in reducing headache frequency in about 40% of patients. Dose: The effective headache dose may be less than is needed for seizures
Adverse effects: Weight gain Transient hair loss Tremor Hepatoxicity - an idiosyncratic reaction that can occur within the first two years of treatment. Nausea, anorexia, vomiting can be first signs of hepatoxicity Category X pregnancy rating when used for the prevention of migraine headaches -- the increased risk of fetal neural defects and a decreased IQ in children who were exposed to valproic acid derivatives while in utero outweighs any migraine prevention benefit
Serotonin receptor agonists (Triptans): Mechanism of action: The triptans are selective serotonin-1D vascular receptor agonists. This reduces the excitability of neurons in the trigeminovascular system, attenuates the release of vasoactive neuropeptides,and causes selective vasoconstriction of cerebral vessels.
Adverse effects: The adverse effects are usually mild and resolve in 30 minutes. The patient can experience a tingling, warm/hot sensation, burning sensation, feeling of heaviness, pressure sensation, feeling of tightness, flushing. With subcutaneous sumatriptan there can be pain or redness at injection site. Rare: Cardiac ischemia (angina) has been reported but it occurs very rarely. Chest symptoms (pressure sensation, feeling of heaviness) occur more often but only rarely are related to cardiac ischemia. Contraindications patients with ischemic heart disease patients who have used ergotamine preparations within the last 24 hours
Serotonin is a neurotransmitter that plays a role in sleep patterns, appetite, nausea, migraine headaches, sexual responses, and regulation of moods There are seven families of 5-HT receptors and 14 receptor sub-types 5-HT1 receptors - stimulation of receptors is associated with antidepressant and anxiolytic effects 5-HT2 receptors - stimulation of receptors is associated with nervousness, insomnia, and sexual dysfunction 5-HT3 receptors - stimulation of receptors is associated with nausea and headache The SSRIs are selective to the 5-HT system but they are not specific in their actions on the different 5-HT receptors
Selective Serotonin Reuptake Inhibitors (SSRIs) Drugs in the Class: Citalopram (Celexa) Escitalopram (Lexapro) Fluoxetine (Prozac) Fluvoxamine (Luvox) Paroxetine (Paxil) Sertraline(Zoloft)
Neuroleptics - Chlorpromazine (Thorazine) and Prochlorperazine (Compazine) These agents antagonize dopamine, cholinergic, and alpha-adrenergic receptors and decrease serotonin reuptake. They have both an anti-emetic effect and they can relieve migraine pain.
Efficacy: For intractable migraines, IV injections of chlorpromazine can be as effective as IV meperidine. Prochlorperazine (Compazine) 25 mg suppositories can also be prescribed for use at home (relief should be noted within 2 hours).
Serotonin/NE Reuptake Inhibitors with 5HT receptor activity Trazodone (Desyrel) Trazodone inhibits the reuptake of serotonin and norepinephrine and is a 5HT-2 antagonist. It also blocks alpha-adrenergic receptors. It has no anticholinergic side effects and no effect on cardiac conduction. It does not appear to be lethal in overdoses. It is sedating and causes orthostatic hypotension. It is seldom used today as an antidepressant because at antidepressant doses, the sedation and orthostasis are problematic. It is used today as an adjunct for sleep in patients taking SSRIs -- the doses used are smaller than doses used in the treatment of depression. Nefazodone (Serzone) Nefazodone inhibits serotonin reuptake and is a serotonin-2 receptor antagonist. It has a low incidence of sexual dysfunction. Its primary adverse effect is orthostatic hypotension. A rare reaction to nefazodone is life threatening hepatoxicity. It should not be used in patients with preexisting liver disease.
5HT Receptor blocker/Alpha2 receptor blocker/Histamine1 blocker Mirtazapine (Remeron) Mirtazipine enhances norepinephrine and serotonin transmission and is a serotonin-2 and serotonin-3 receptor antagonist. It has a low incidence of sexual adverse effects and gastrointestinal adverse effects, but can cause weight gain. Pediatric Note: All of the antidepressants carry a warning about suicidality in children. The warning says: " Antidepressants increased the risk of suicidal thoughts and behaviors in patients aged 24 years and younger in short-term studies. Monitor closely for clinical worsening and for emergence of suicidal thoughts and behaviors."
Management of Pain in Geriatrics
A nonverbal elderly adult will need to have their pain assessed via direct observation or history from caregivers. Common pain behaviors in cognitively impaired elderly persons include: grimacing face, wrinkled forehead, sighing, moaning, groaning, rigid, tense body posture, fidgeting, decrease in social interactions, changes in mental status. The PAINAD scale can be used to quantify these observations. Older patients may be reluctant to report pain to caregivers because of a fear of diagnostic procedures or medicines, or a cultural need to appear stoic. They may, however, acknowledge discomfort, hurting or aching. The American Geriatrics Society Panel on Persistent Pain in Older Adults recommends that on initial presentation or admission, all older persons be screened for pain. If pain is present, the patient should undergo a comprehensive pain assessment, with the goal of identifying all potentially remediable factors. Older patients are generally more susceptible to adverse reactions and may be more sensitive to central nervous system effects of drugs. If opioids are used in the elderly, the initial doses should be smaller and titrated upward if necessary. Meperidine should be avoided (or used with caution) in the elderly because renal function declines with age and the metabolite, normeperidine, can accumulate. When opioids are used in the elderly, the clinician should monitor carefully for adverse effects. Gait impairment, ataxia, dizziness and falls can occur. The elderly are especially prone to constipation from opioids; the clinician should address this early if the patient is taking an opioid for more than one to two days.
Abortive Therapy for Migraine Headaches Specific therapy for migraine headaches generally are medications that interact with the serotonin system in the CNS. The medications include the triptans and ergotamines. The use of these agents should be limited to 2-3x/week. If more frequent use is needed, the patient needs prophylactic therapy also. (p. 625-627) (p. 535, ch. 35)
Abortive Therapy for Migraine Headaches Specific therapy for migraine headaches generally are medications that interact with the serotonin system in the CNS. The medications include the triptans and ergotamines. The use of these agents should be limited to 2-3x/week. If more frequent use is needed, the patient needs prophylactic therapy also.
Acute Pain
Acute pain occurs immediately following an injury to the body. It is usually self-limiting and subsides when the injury heals. Inadequately treated acute pain can produce tachypnea, tachycardia, induce a stress response in the body leading to endogenous corticosteroid release, and thus delay recovery after surgery or trauma. Acute pain should be aggressively managed and will usually respond to opioid therapy.
Geriatric note: All benzodiazepines are listed in the Beers Criteria of Potentially Inappropriate Drugs in the Elderly. They increase the risk of cognitive impairment, falls, and fractures. If a benzodiazepine must be used in an elderly patient, use the smallest dose possible for the shortest period of time.
Adverse effects Sedation and feelings of tiredness Cognitive impairment - may present as dementia in the elderly Psychomotor impairment - may increase risk of car accidents (you must counsel about this and the patient must be warned to avoid alcohol) Memory impairment - may affect the ability to acquire or store recent information. Is a desired effect when these agents are used for pre-op sedation. Is not a desired effect when these agents are used by a business traveler for jet lag. Respiratory depression - not usually a problem when these agents are used in therapeutic doses. However, you should be cautious if prescribing to patient with sleep apnea.
The SSRIs increase synaptic concentrations of serotonin by selectively blocking reuptake of serotonin at the presynaptic terminal. This partially explains the SSRI mechanism of action, but does not entirely explain their effect on depression. The reuptake inhibition occurs immediately and the level of neurotransmitters in the brain changes immediately; however, it is well known now that the antidepressant effect of the SSRIs doesn't occur for several weeks after starting these agents. This suggests that the antidepressants effects are not only related to the amounts of neurotransmitters, but also to the sensitivity of the receptors themselves.
Adverse effects of SSRIs common to the whole class of drugs (they are related to the increase in serotonin): anorexia nervousness/agitation insomnia, nausea diarrhea headache sexual dysfunction Drug Interactions: Pharmacokinetic drug interactions - Enzyme Inhibition: SSRIs inhibit isoenzymes of the cytochrome P450 system. Fluoxetine and fluvoxamine inhibit several different isoenzymes and may therefore decrease the clearance of many drugs metabolized by this system. Paroxetine and sertraline inhibit only one isoenzyme; citalopram shows little enzyme inhibition. Pharmacodynamic drug interactions - Serotonin Syndrome: SSRIs increase serotonin; when given with other drugs that increase serotonin, serotonin syndrome can result. Symptoms of serotonin syndrome include hyperpyrexia, hypertension, and seizure. Some of the other drugs that increase serotonin include MAOIs, lithium, carbamazepine, tramadol, linezolid, and meperidine.
Geriatric note
All of the NSAIDs are included in the Beer's List of Medicines to avoid if possible in the elderly. The primary reason is because of the possibility of gastrointestinal bleeding and it is recommended to avoid chronic use unless other alternatives are not effective and gastrointestinal protection (e.g. proton pump inhibitor) can be taken. Indomethacin carries an additional caution because it can cause CNS adverse effects, primarily sedation. Indomethacin is not a good choice in the elderly.
TCA Side effects and their management: The side effects of the various tricyclic agents varies with their structure. Clinical uses of the TCAs TCAs are used in: Depression Trigeminal and post-herpetic neuralgia Diabetic neuropathy Enuresis Migraine prophylaxis Geriatric Note: The first generation tricyclic antidepressants (amitriptyline, desipramine, nortriptyline, etc) are on the Beers List of medications to be avoided in the elderly because they are sedating, anticholinergic, and cause orthostatic hypotension. The SSRIs (except paroxetine), SNRIs, or bupropion are safer alternatives to treat depression in the elderly.
Anticholinergic side effects can be the most troublesome side effects of this class of drugs. dry mucous membranes constipation blurred vision urinary hesitancy Neurologic Sedation - desipramine and protriptyline are less sedating than the other TCAs and are a good choice if sedation is a concern. The sedating TCAs should be given at night. Lowers seizure threshold - this may make an underlying seizure disorder more difficult to treat. It is also one of the catastrophic events that occurs in a TCA overdose May worsen psychosis in schizophrenia - use with caution in a patient with schizophrenia Cardiovascular Orthostatic hypotension - Patients most at risk for this are the elderly, those with CHF. Prolonged conduction in heart - all the TCAs can prolong cardiac conduction through the His-Purkinje system. This can lead to arrhythmias. Patients with a pre-existing cardiac conduction defect are most suspectible to this adverse effect at theraputic doses of TCAs. In overdoses, fatal cardiac arrhythmias are the most common cause of death. TCAs are lethal when taken in overdose. The amount needed for lethality can be relatively small (a one month supply of a therapeutic dose of amitriptlyine can easily be lethal), so when prescribing these agents you should also take this into consideration. Miscellaneous Weight gain - all the TCAs can cause weight gain
Tricyclic Antidepressants Amitriptyline (Elavil) Imipramine Nortriptyline Doxepin (Sinequan) Trimipramine Protriptyline (Vivactil) Desipramine Mechanism of action: The tricyclic antidepressants inhibit the neuronal reuptake of norepinephrine and serotonin into presynaptic nerve terminals.
As with the SSRIs, the this partially explains the TCAs mechanism of action, but does not entirely explain their effect on depression. The reuptake inhibition occurs immediately and the level of neurotransmitters in the brain changes immediately; however, it is well known now that the antidepressant effect of the TCAs doesn't occur for several weeks after starting these agents. This suggests that the antidepressants effects are not only related to the amounts of neurotransmitters, but also to the sensitivity of the receptors themselves.
Efficacy of Antidepressants All classes are approximately equal in efficacy when used in appropriate doses 65-70% patients will improve with antidepressants (30-40% will improve with placebo).
Augmentation Therapy Augmentation therapy is adding another drug to an antidepressant for patients who exhibit partial response to their first antidepressant. Choices for augmentation include: Another antidepressant in a different class -- e.g. if an SSRI was started, then add a SNRI. Lithium Buspirone Triiodothyronine (T3) Second generation antipsychotic - aripiprazole (Abilify), quetiapine (Seroquel), brexpiprazole (Rexulti)
Clinical Uses of SSRIs: Serotonin is an important neurotransmitter involved in the pathophysiology of many psychiatric disorders. The SSRIs are used to treat: Depression Obessive-Compulsive Disorder Panic Disorder Premenstrual dysphoria Social Phobia PTSD Chronic pain management Migraine headache prophylaxis
Geriatric Note:Paroxetine is on the Beers List of medications to be avoided in the elderly because it is more sedating and has more anticholinergic activity than the other SSRIs. Another SSRI is a safer alternative. Pharmacoeconomics Note: Many of the SSRIs are available as generics and are very inexpensive (e.g. citalopram, fluoxetine, paroxetine are about $15/month). Fluoxetine has a very long half life and it is available in a once weekly formulation (Prozac weekly); this option is expensive - $180/month compared to $15/month for daily tablets.
Benzodiazepines in Insomnia Considerations in choosing a benzodiazepine Time of onset - quick versus slow. You should determine whether the patient has difficulty in falling asleep or difficulty in staying asleep. You can then tailor your choice of drug more appropriately. Flurazepam (Dalmane) and Triazolam (Halcion) are examples of benzodiazepines that have a quick onset. Temazepam (Restoril) is an example of a benzodiazepine that takes 45 minutes or more to work, and isn't a good choice for difficulty in falling asleep. Duration of action - longer acting more likely to accumulate and cause hangover, but is desirable if daytime anti-anxiety effect is needed. Flurazepam (Dalmane) is an example of a longer acting agent.
Benzodiazepine Receptor Agonists -do not have a benzodiazepine structure so are called non-benzodiazepine hypnotics. They act on the benzodiazepine receptors (GABA - A) receptors in the brain. Zolpidem (Ambien) - has a duration of action of 6 to 8 hours. If sleep maintenance is the issue, a controlled release form is available with a longer duration of action. If middle of the night wakening is the issue, there is a very shorting acting form (Intermezzo- zolpidem sublingual) available. Zaleplon (Sonata) - has a quick onset of action, and a shorter duration of action. Helps patients fall asleep but is less effective in maintaining sleep. Eszopiclone (Lunesta) - has a quick onset of action and a duration of action of 6 hours. It is labeled for long-term use (up to 6 months).
Benzodiazepine abuse - all patients who take chronic, long term benzodiazepines will experience withdrawal symptoms if the drug is stopped abruptly. Only a few will abuse benzodiazepines. Abuse is: Recreational use Dose escalation Loss of control over use: More likely to occur with benzodiazepines with quick onset (e.g. diazepam) More likely to occur in patients with current or past history of other substance abuse The most important drug interactions with the benzodiazepines are pharmacodynamic. The benzodiazepines act as CNS depressants and will cause increase sedation and psychomotor impairment when used with other CNS depressants, including alcohol.
Benzodiazepine withdrawal Patients at risk Abrupt discontinuation of benzodiazepines Duration of therapy >3 months High doses
Other Medications Used for Anxiety Besides the benzodiazepines, other commonly used anti-anxiety medications include buspirone, TCAs, MAOIs, and SSRIs Buspirone (Buspar) Mechanism of action: Buspirone is serotonin 1A partial agonist. It is used in the treatment of chronic anxiety and anxiety with depression. It has little sedative activity, does not impair psychomotor function, and is not addictive. Adverse effects: nausea, dizziness, headache, nervousness Onset of anxiolytic activity: 1 week. Maximal response: 4 - 6 weeks
Beta-blockers May reduce symptoms of anxiety (tachycardia, tremor) but don't affect the mental symptoms of anxiety Tricyclic Antidepressants Tricyclic antidepressants are second-line agents in the management of various anxiety states. Monoamine Oxidase Inhibitors MAOIs are 2nd or 3rd line agents in the management of anxiety, especially panic disorder. Selective Serotonin Reuptake Inhibitors (SSRIs) The SSRIs are effective in the management of many anxiety disorders, particularly obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, and social phobia. Many clinicians will use SSRIs as the drugs of first choice for these disorders.
Propranolol (Inderal), metoprolol (Lopressor) and timolol (Blocadren)
Beta-blockers are the drug of first choice in migraine preventive therapy because they have proven efficacy and fewer adverse effects as compared to the other Level A agents. Blockade of beta-1 receptors lead to secondary effects on serotonin. 70 to 80% of patients will obtain complete or partial relief
Adverse effects of opioids
CNS depression - especially with large doses. Drowsiness, sedation, mood changes, disorientation, and memory impairment can occur. Respiratory depression - a dose related adverse effect. It occurs because of direct action on the brain respiratory centers; this causes reduced responsiveness to carbon dioxide in the blood. It is especially a concern in the patient with COPD or other respiratory disease. Tolerance to respiratory depression develops rapidly so it is usually not a dose limiting adverse effect when titrating doses upward in the treatment of persistent pain. Emesis - directly stimulates the chemoreceptor trigger zone and can cause vomiting Gastrointestinal tract - decreases the motility of the gastrointestinal tract and causes constipation. Patient's do not develop tolerance to this adverse effect and it is a common, clinically significant adverse effect in both patient's taking opioids for the short term treatment of pain, and in patient's taking opioids to treat persistent pain. Prevention is the best management strategy; the use of twice daily stool softener/stimulant laxative such as senna or docusate/bisacodyl is recommended. Urinary retention - opioids increase smooth muscle tone in the bladder and ureters and can cause urinary retention because of an increase in sphincter tone. Pruritis - opioids can cause pruritis. It is thought to occur secondary to a release of histamine from mast cells. Treatment with an antihistamine such as diphenhydramine will decrease the pruritis. CNS Irritation - CNS irritability as manifested by tremors, twitching and even seizures can occur. It most likely to happen when the active metabolite of meperidine accumulates in renal dysfunction but can also occur with morphine, in the setting of renal dysfunction. Tolerance - repeated use produces tolerance to the respiratory depressant, analgesic, euphoric, and sedative effects of the opioids. Physical dependence - Sudden withdrawal from the opioids can cause a characteristic withdrawal syndrome that includes tachycardia, sneezing, restlessness, hallucinations, and tremors. Other signs and symptoms of withdrawal include nausea, vomiting, diarrhea, watery eyes, yawning, and a runny nose. Methadone carries special warnings. Because of its long half life, it takes longer to get to steady state and takes longer to be eliminated from the body. It can accumulate and cause significant respiratory depression, especially during a dose titration. In addition, it can affect the QT interval and predispose to arrhythmias. Methadone Risk Mitigation
Drugs that may be effective - evidence for efficacy has been shown only in single or small trials - Level C ACE inhibitors and ARBs Candesartan Lisinopril
Carbamazepine Antiseizure medication that is also used to treat neuropathic pain May be tried in migraine prevention but there is less evidence that it works for migraines
Migraine headaches that have not responded to NSAIDs or Excedrin Patients with migraine headaches that haven't responded to NSAIDs or Excedrin should receive migraine specific therapy such as a triptan or dihydroergotamine. Also, if a patient has a history of headaches that don't respond to NSAIDs, you might want to begin with migraine specific therapy.
Choosing the Agent - The process of choosing the appropriate therapy can be a trial and error process. Some patients will respond to one agent, or dosage form and not another. Oral triptan - if headache isn't quick onset and patient isn't vomiting Nasal Sumatriptan or Nasal DHE -- May be useful in patient who vomits with headache but doesn't need quickest onset of action SQ Sumatriptan - quickest onset of the triptans, but is an injectable agent Oral Narcotic Analgesics - may be needed for patients who can't take any of the above medications. Combination products (e.g. Fiorinal) are a good choice but remember the acetaminophen content (don't want to exceed max daily doses of acetaminophen) Nausea and Vomiting Metoclopropamide (Reglan) orally is a useful adjunct for nausea Rectal neuroleptic (e.g Prochlorperazine - Compazine- suppository) can treat the nausea and vomiting and also help headache pain Rescue Medications (Self administered at home) Patients can be given a prescription for a self-administered rescue medication for when the above therapy hasn't worked. The medication can be a narcotic analgesic such as one of the many combination products available (e.g. Lorcet, Fiorinal, Percocet). If this medication needs to be used frequently, you should reevaluate the treatment regimen and begin preventive therapy or reevaluate your preventive therapy.
Insomnia is a perceived relative decrease in the quantity and/or quality of sleep. Twenty-five to 35% of the adult population will complain of sleep disturbances at one time or another. (p. 631-636) Sleep Physiology Sleep is divided into nonrapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. NREM sleep serves to restore, rejuvenate, and revitalize the body. It is divided into 4 stages -- stage 1 and 2 are lighter sleep and stage 3 and 4 are the deep, restorative sleep stages. REM sleep is similar to stage 1 sleep, except that in REM sleep there are burst of bilateral rapid eye movements; dreams occur during REM sleep. Young adults typically spend about 75% of the night in NREM sleep and 25% in REM sleep. As we age, the time spent in stage 3 and 4 sleep tends to decrease.
Classification of Insomnia Transient insomnia · normal sleepers who are reacting to some acute and environmental stress. Lasts from one to a few days. · hypnotics most effective in these patients Short-term insomnia · insomnia resulting from a major life stress (loss of job, death, divorce) that lasts up to 3 weeks Chronic Insomnia · insomnia lasting from months to years. Often associated with depression, anxiety disorders, ethanol abuse
Rebound Headaches Acute therapy of headache should be limited to two days a week if at all possible because frequent use of analgesics, ergotamine and sumatriptan can lead to rebound headaches.
Clinical Characteristics of Rebound Headache Headaches are daily or nearly daily Headaches occur in patient with migraine headache who uses abortive therapy frequently Headache varies in type, severity and location The slightest amount of physical or mental effort may precipitate the headache Evidence exists of tolerance over time, with need for larger doses of medication Withdrawal symptoms are observed when pain meds are withheld abruptly Concomitant preventive medications are relatively ineffective Management of rebound headache requires the slow withdrawal of the daily use of headache medications. It will require patient education and cooperation. The headaches will worsen for 24-48 hours and it may take 8-12 weeks for normal responsivesness to appropriate therapy to return.
Acetaminophen (Tylenol) (p.526-527, p. 891-895) Acetaminophen is a non-narcotic (it won't cause physical dependence or tolerance) analgesic that acts by inhibiting prostaglandin synthesis in the CNS. The inhibition of prostaglandin in the CNS gives it analgesic and antipyretic activity. It does not inhibit prostaglandin in the peripheral tissues and therefore, has weak anti-inflammatory activity. Adult Doses: up to 1 gram four times daily (maximum recommended daily dose is 4 grams). If used chronically, maximum daily dose should be <2600 mg/day.
Clinical Use: Effective and inexpensive analgesic that is recommended as first line therapy for mild-moderate pain. A trial of 4 to 6 weeks at 4 grams/daily (lower max if patient has renal or hepatic impairment or consumes >2-3 drinks/day of alcohol) is recommended before deciding that the the pain is not responding to acetaminophen. Acts as an adjunct to opioid pain medications, increasing pain control at lower opioid doses. Adverse effects: well tolerated by most patients
Dihydroergotamine (DHE) is an ergot derivative that causes less nausea than ergotamine Available as IV, IM, or SC. Also available as Nasal DHE (Migranal)
Clinical Use: Nasal DHE (Migranal) is an alternative to nasal sumatriptan -- some patients will respond to one and not another. SQ DHE is an alternative to SQ sumatriptan - patients can administer it at home also. It appears to be less effective than SQ sumatriptan but may be useful in some patients IV DHE is useful in the management of intractable migraines. It causes nausea and vomiting in almost all, so administer an anti-emetic at the same time. Contraindications - same as with ergotamine
Pathophysiology of Migraine Headache and Serotonin Receptors Release of vasoactive substances from nerve fibers in the CNS induce a sterile inflammatory reaction around blood vessels in the brain Neurogenic inflammation may be accompanied by vasodilation 1D receptor (5-HT1D ) subtype is an inhibitory serotonin receptor and stimulation of this receptor will decrease the neurogenic inflammation 2 receptor (5-HT2 ) subtype is excitatory and activation of this receptor can lead to increased migraine symptoms.
Clinically, many of the drugs that we use to specifically treat an acute migraine headache act to activate the 5-HT1D receptors, while many of the drugs used as migraine prophylaxis block the 5-HT2 receptors.
Criteria for prophylaxis (p.540-541) disabling headaches that don't respond to abortive measures patients in whom ergots or triptans are contraindicated headaches that occur in predictable patterns headaches which occur twice monthly or more
Considerations in prophylaxis: Patients should understand that less than 10% of migraine patients become headache-free with prophylaxis. A realistic goal is 50% reduction in frequency and severity of headaches It can be 2-6 months before benefit is noted
Topiramate (Topamax) Topiramate is an anti-seizure medicine that has also been shown to be effective in decreasing the frequency of migraine headaches.
Controlled trials suggest that it is as effective as divalproex (Depakote) Adverse effects include paresthesia, fatigue, nausea, and anorexia Is now available generically, so the cost is reasonable
Instructor note
Cox-2 inhibitors appear to cause an increased risk of cardiovascular events. Rofecoxib ( Vioxx ) was removed from the market in 2004 because study data showed that patients taking it had a higher risk of heart attack and stroke. Valdecoxib ( Bextra ) was removed from the market in 2005 because in addition to the concerns of increased cardiovascular disease risk, it also caused a higher incidence of serious skin reactions (including Stevens-Johnson syndrome) than the other drugs in the class. Celecoxib ( Celebrex ) remains on the market but it is recommended that it be used in doses of ≤ 200 mg/day, for as short of time as possible. The mechanism for the increased risk of cardiovascular events is thought to be that selectively inhibiting COX-2 may suppress endothelial cell synthesis of prostacyclin , thus leaving platelet thromboxane A2 mediated by COX-1 unopposed, leading to vasoconstriction , platelet aggregation, and thrombosis.
Anxiety is an unpleasant feeling of apprehension or fearful concern. It can be a normal and reasonable response to a stressful situation or it can be excessive and irrational. Anxiety disorders are generally chronic and recurring and treatment may not completely eliminate symptoms. - 80% of patients with generalized anxiety disorder have at least one other anxiety disorder.
DSM-V Classification of Anxiety Panic disorders (with or without agoraphobia) Phobic disorders (specific phobia, social phobia, agoraphobia) Obsessive-compulsive disorders (OCD) Post-traumatic stress disorder (PTSD) Generalized anxiety disorder (GAD) Acute stress disorder Anxiety disorder due to a general medical condition Substance-induced anxiety disorder Anxiety disorder not otherwise specified
Diagnostic Criteria for Major Depression (from the American Psychiatric Association Diagnostic and Statistical Manual, 5th ed 2013) At least five of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either depressed mood or loss of interest or pleasure. The mood disturbance also must cause marked distress or a clinically significant impairment in social or occupational functioning
Depressed mood Markedly diminished interest or pleasure in all, or almost all, activities Significant weight loss or weight gain, or decrease or increase in appetite Insomnia or hypersomnia Psychomotor agitation or retardation Decreased libido Fatigue or loss of energy Feelings of worthlessness or excessive or inappropriate guilt Diminished ability to think or concentrate, or indecisiveness Recurrent thoughts of death, recurrent suicidal ideation, or a suicide attempt or a specific suicide plan
Uses for benzodiazepines FDA approves the labeling of drugs, and the indications listed in the package insert for a particular drug reflect the studies submitted by the manufacturers to the FDA. This can reflect marketing issues as well as therapeutic issues. All the currently available benzodiazepines act on the same BZ receptors. The differences between them are pharmacokinetic - absorption, distribution, metabolism. Benzodiazepines are useful for: Anxiety Insomnia Alcohol withdrawal Anticonvulsants Pre-op sedation Anesthesia induction Muscle spasms Panic disorder
Differences Among the Benzodiazepines Onset of effect Drug's rate of absorption determines onset of effect. Faster onset is important in treatment of acute situations. Faster onset may be related to feeling of euphoria, "rush" . Benzodiazepines with fast onset include diazepam, midazolam Metabolism - Long-acting versus short-acting Most benzodiazepines, including diazepam and flurazepam undergo hepatic microsomal oxidation followed by hepatic glucuronide conjugation. Oxidation may be impaired in liver disease, elderly and with interacting drugs. Lorazepam and oxazepam are eliminated through glucuronide conjugation alone, and don't accumulate in above situations. Long-acting agents: May be useful for chronic conditions (ie chronic anxiety) but may accumulate,especially in elderly. Long acting agents include diazepam and flurazepam. Short-acting agents: Less accumulation and useful for acute situations. Lorazepam and midazolam are shorter acting agents.
Ergotamine Tartrate (Cafergot): The ergotamine derivatives are the classic medications used in the treatment of acute migraine. Guidelines from the American College of Physicians/American Academy of Family Physicians (Snow V, Weiss K,et. al. Ann Intern Med 2002;137:840-849) recommend not using ergotamine because the evidence indicating efficacy is inconsistent and it is accompanied by many side effects. The ergotamines act in migraine headaches by activating the 5-HT1D receptors. They are not specific to these receptors and also have vasoconstrictive properties.
Dosage: Ergotamines must be given at the first sign of headache or aura. The most effective dose is a subnauseating dose (it may take some trial and error to determine this). Because it acts as a vasoconstrictor and large doses can cause serious side effects you MUST discuss maximum dosages with the patient. Maximum doses for ergotamines are 6 mg/attack or 10 mg/week. Contraindications: heart disease arterial or venous insufficiency sepsis pregnancy Co-administration with potent CYP 3A4 enzyme inhibitors such as macrolide antibiotics (e.g. erythromycin), protease inhibitors (e.g. ritinovir), or azole antifungals (e.g. ketoconazole, itraconazole). Adverse effects of ergotamines: Nausea, vomiting, anorexia. Manage: Metoclopropamide (Reglan) 10 mg - take as soon as possible (ie with the ergotamine) Peripheral vasoconstriction Overuse can lead to cyanosis, claudication, gangrene of limbs (don't forget to warn of maximum doses to be used!) Metoclopropamide (Reglan) is a Serotonin3 antagonist and is useful as an adjunct in the management of migraine headache. Stimulation of 5-HT3 receptors causes nausea and vomiting and metoclopropamide will help alleviate this.
Onset of Action Up to 4 weeks until full antidepressant effects are noted Some symptoms may improve earlier Choosing an agent SSRIs and the newer agents have fewer adverse effects than TCAs and MAOIs and are generally first-line therapy. Choose among SSRIs and newer agents according to cost, and adverse effects. Change if adverse effects are bothersome. Use MAOIs only for patients who do not respond to other treatments.
Duration of Therapy of Therapy for Major Depression Acute phase 6-8 weeks at full therapeutic doses Continuation phase Additional 4-9 months at full therapeutic doses Maintenance Phase - consider long-term therapy for: Any patients who has had 3 or more depressive episodes. A patient over age 50 who has had two or more depressive episodes A patient over age 60 who has had one or more previous depressive episodes Discontinuing Antidepressants The antidepressants should be gradually tapered when they are discontinued.
Pain Rating Scales Pain rating scales should be easy to use for both clinicians and patients and should be developmentally appropriate. For adults and older children, a numerical rating scale is most commonly used. The patient is asked to give a numerical rating to their pain, with 0 being no pain and 10 being the worst pain. For children who can not count, the Wong-Baker faces scale is often used.
For the elderly with severe dementia, the Pain Assessment in Advanced Dementia (PAINAD) scale can be used. This assesses breathing, vocalization, facial expression, body language and consolability to assign a pain score. A disadvantage of this tool is that the patient must be observed for 3 to 5 minutes. A useful scale for assessing chronic pain is the PEG scale. This is a three question scale that assesses pain intensity, effect of pain on enjoyment of life, and effect of pain on the activities of daily living.
Adverse effects: NSAIDS
Gastrointestinal: Prostaglandin is necessary for maintaining the gastric mucosa and inhibiting the formation of prostaglandin will predispose to gastrointestinal disturbances. Up to 60% will experience nausea, dyspepsia, heartburn with any of these agents. Renal: Prostaglandins maintain renal blood flow, especially when there is systemic vasoconstriction. Inhibition of prostaglandins can leave the vasoconstrictors to act in an unopposed fashion, and you can see acute renal failure. Especially at risk for acute renal failure secondary to NSAIDs: CHF, liver disease, concomitant diuretics Bleeding time: Aspirin irreversibly acetylates platelets and increases bleeding time. Non-ASA salicylates and NSAIDs inhibit platelet aggregation, but effect is reversible.
opioid conversion calculator
Global Rph is a good website that contains many handy drug calculators. The opioid conversion calculator is a very convenient way to determine an reasonable dose when you are converting from one opioid to another.
Treatment Approaches to Migraine Headache Migraine headaches are often accompanied by nausea and vomiting.You must take into account the patient's gastrointestinal status before deciding on acute therapy. Even if the patient is not vomiting, decreased gastric motility may be present and must be managed before oral therapy can be absorbed. The treatment approach below was adapted from Gilmore B and Michael M Treatment of Acute Migraine Headache Am Fam Physician
Goals of Therapy Treat the acute attack rapidly and consistently Restore the patient's ability to function Minimize the use of backup and rescue medications Mild Migraine Headache without vomiting First line therapy for most patients with migraines should be either: A NSAID - aspirin, ibuprofen, and naproxen sodium have the most evidence for efficacy in migraines. Acetaminophen/Aspirin/Caffeine (Excedrin) - clinical studies have shown that it is effective in the treatment of migraine headaches. Metoclopramide (Reglan) for nausea.
Duration of Therapy in the management of insomnia Drug therapy for insomnia is most successful for transient or short term insomnia. In general, drugs for insomnia work best when used in cycles of 5-7 days. Use can be repeated during stressful times, with drug-free periods of at least one week.
Herbal Remedies Valerian Valerian is an herb native to North America, Asia, and Europe. Mechansim of action Valerian root contains the volatile oil, valeric acid, alkaloids, and free amino acids such as GABA, tyrosine, arginine, and glutamine. Valeric acid demonstrates direct sedative effects; it also interacts with the GABA neurotransmitter. Clinical Use Several clinical studies have shown that compared to placebo valerian may be effective in treating insomnia by reducing sleep latency. It has also been used as an anxiolytic. Adverse effects Valerian is well tolerated with few reported adverse effects. It may potentiate the sedative effects of other CNS depressants such as ethanol. Melatonin Melatonin is a hormone produced by the pineal gland. At night, melatonin secretion increases thus promoting sleep. Mechanism of action Synthetic melatonin acts just like natural melatonin. Clinical Use Melatonin may improve sleep, particularly for patients in whom circadian sleep patterns are disrupted (delayed sleep phase syndrome). Other studies (in patients without delayed sleep phase syndrome) have found limited benefit from melatonin. Adverse effects Fatigue and depression have been reported with melatonin.
Chronic Pain
Is also called persistent pain. The term chronic pain has been associated with negative connotations including perceptions of malingering, drug-seeking behavior, psychiatric problems, so the American Geriatrics Society recommends using the term persistent pain. Chronic pain usually serves no benefit to the individual. It can be episodic or continuous and can lead to a deteriorating quality of life, including impairments in functional ability, interpersonal relationships, spiritual well-being, and financial status. Chronic pain management often requires multiple modalities, including behavior interventions, physical interventions, and pharmacologic therapy. Chronic pain can be further divided into chronic malignant pain and chronic non-malignant pain
Opioids (p.527-531)
Mechanism of Action The opioids bind to opioid receptors in the CNS and the gastrointestinal tract. In addition, they decrease the release of substance P and inhibit the release of other excitatory transmitters from nerve terminals carrying painful stimuli. Mu, Kappa, and Delta opioid receptors are present in high concentrations in the dorsal horn of the spinal cord. Opioid agonists inhibit both the neurons that deliver pain impulses to the spinal cord and also inhibit the transmission of pain impulses from the spinal cord to the brain. Directly administering opioid agonists to the spinal cord provides analgesic effect with less respiratory depression, nausea and vomiting, and sedation. They produce analgesia by raising the pain threshold at the spinal cord level and by altering the brain's perception of pain. Patients are still aware of the presence of pain but the sensation is not unpleasant. Additionally, these drugs suppress the cough reflex.
Etiology of Major Depressive Disorder The etiology of major depressive disorder is not clear. One theory is called the: Dysregulation hypothesis It states that depression occurs when brain neurotransmission isn't properly regulated--the balance between norepinephrine, serotonin, and receptor sensitivity is disturbed. The drugs that we use to treat depression act to alter the neurotransmitter levels in the brain and also affect the receptor sensitivity. Other factors that can influence depression: Hypothalmic-pituitary-adrenal axis -- Patients with depression may have alterations in their HPA axis. Thyroid hormone and growth hormone responses may also be altered in patients with depression. (p.583-594)
Medications that may induce Depression Selected Medications That May Induce Depression Cardiovascular Agents β-blockers (?) Clonidine Methyldopa Reserpine Central Nervous System Agents Barbiturates Benzodiazepines (?) Chloral hydrate Ecstasy (MDMA) Ethanol Hormonal Agents Anabolic steroids Corticosteroids Gonadotropin-releasing hormone Progestins Tamoxifen Others Efavirenz Interferon Isotretinoin Mefloquine Levetiracetam
Orexin receptor blocker Suroxevant (Belsomra) is a orexin receptor antagonist. Orexin is a central promoter of wakefulness and blocking orexin suppresses the wake drive. Can be used in patient's with difficulties with sleep onset or sleep maintenance. Is not more effective than other agents, but is an alternative to be tried.
Melatonin Agonist Ramelteon (Rozerem) is a selective melatonin agonist with a short onset of action. Because it is a melatonin derivative, it is most appropriate for the management of insomnia associated with either jet lag or shift work. Antidepressants If a patient is depressed, treatment of depression usually improves sleep pattern. Sedating TCA's such as amitriptyline (Elavil) or doxepin (Sinequan) have been used in lower doses to treatment insomnia, although there are few controlled studies to support this use. Trazodone in low doses is sedating and can improve sleep when given at bedtime Antihistamines Available as non-prescription sleeping aids (ie Sominex) Not as effective as benzodiazepines Anticholinergic side effects - dry mouth, constipation
Geriatrics Note:
Meperidine (Demerol) is metabolized to normeperidine. Normeperidine accumulates in patients with renal dysfunction and can cause CNS stimulation and seizures. Other analgesics are preferred in the elderly and those with renal dysfunction. Meperidine is on the Beers Criteria list of medications to be avoided or used with caution in the elderly.
Classification of Headaches (p.535-537)
Migraine Migraine without aura Migraine with aura Complicated migraine Tension-Type Headache Episodic tension-type headache Chronic tension-type headache Cluster Headache Episodic cluster headache Chronic cluster headache Miscellaneous Headaches Unassociated with Structural Lesion (e.g., cold stimulus headache, benign exertional headache) Headache Associated with Head Trauma Acute post-traumatic headache Chronic post-traumatic headache Headache Associated with Vascular Disorders Acute ischemic cerebrovascular disease (TIA or stroke) Intracranial hematoma Subarachnoid hemorrhage Unruptured vascular malformation Arteritis Carotid or vertebral artery pain Venous thrombosis Arterial hypertension Headache Associated with Nonvascular Intracranial Disorder (e.g., high or low CSF pressure, intracranial infection, or neoplasm) Headache Associated with Substances or their Withdrawal (e.g., withdrawal from alcohol, caffeine, ergotamine, narcotics). Headache Associated with Noncephalic Infection (e.g., viral or bacterial infection) Headache Associated with Metabolic Disorder (e.g., hypoxia, hypercapnia, hypoglycemia, dialysis) Headache or Facial Pain Associated with Disorder of Cranium, Neck, Eyes, Ears, Nose, Sinuses, Teeth, Mouth, or Other Facial or Cranial Structures (e.g., cervical spine, acute glaucoma, refractive errors, acute sinus headache) Cranial Neuralgias, Nerve Trunk Pain and Deafferentation Pain (e.g., compression, demyelination, infarction, or inflammation of cranial nerves) Headache Not Classifiable
Opioids in Pediatrics
Morphine pharmacokinetics differ in preterm and term neonates as compared to older infants. A term neonate of less than 4 days of age will have an elimination half-life of morphine that is significantly longer than an older infant leading to increased morphine plasma levels. A preterm neonate has an even slower clearance rate than a term neonate. This leads to differing dosage recommendations for preterm, term, and older infants. Fentanyl is another opioid analgesic used in infants. It has an increased volume of distribution in term and preterm neonates, and thus a lower peak plasma level after bolus dosing as compared to that found in older infants. The clearance rate is lower in the preterm and term neonate, so doses of the drug (on a mcg/kg basis) should be lower in the preterm and term neonate Opioids can cause respiratory depression in infants. The clinician should carefully monitor for this adverse effect. Signs of respiratory depression from opioids can include: Unresponsiveness, and a decrease in respiratory rate.
Drugs that are probably effective but there is less evidence for efficacy in clinical trials - Level B Amitriptyline (Elavil) Dose: 25 to 150 mg/day Tricyclic Antidepressants (TCAs) have been shown effective in reducing the frequency of both migraine and tension headaches As you approach 100-150 mg/day, anticholinergic adverse effecs become dose limiting.
NSAIDs Ibuprofen, Ketoprofen, Naproxen, and Fenoprofen are all options They should be administered on a scheduled basis when used as a prophylactic medicine
Pregnancy Note:
NSAIDs are generally considered to be relatively safe in early pregnancy (although use should be avoided if possible). There have been several population based studies of large numbers of pregnancies and there was no signficant increase in musculoskeletal or cardiac malformations in first and second trimester exposures. In the third trimester, the NSAIDs pose greater risk. Inhibition of prostaglandin synthesis in the third trimester may cause premature closure of the ductus arteriosus which can lead to fetal pulmonary hypertension and right ventricular heart failure. Women should not take NSAIDs after the 30th week of pregnancy.
Reversing the effect of opioid analgesics:
Naloxone (Narcan) is a mu receptor antagonist Administered parenterally. Will completely reverse the effects of morphine within 1-3 minutes; can precipitate withdrawal symptoms in an opioid dependent patient. Has a short duration of action (1-2 hours) so may need to be given continuously in the treatment of a longer acting opioid overdose. There is a campaign to provide at home naloxone rescue kits for family members to use in patients at high risk for opioid overdose. The kit contains injectable naloxone and a system to administer the drug nasally. The naloxone is effective when given intranasally. For more information see: Prescribe to Prevent Peripheral Mu Receptor Antagonists antagonize the mu receptor but do not cross the blood brain barrier; this allows them to antagonize opioid effects in periphery without decreasing the central analgesic effects. They are used to treat opioid induced constipation Methylnaltrexone (Relistor) It is given as a subcutaneous injection; it can be given on a daily basis if needed Naloxegol (Movantik) is an oral tablet given once daily
narcs for migraines
Narcotic Analgesics - Will also relieve intractable migraine pain, but are generally reserved for second or third line therapy after patients have failed to respond to one of the above treatments.
The NSAIDs are classified according to their structure. Clinically, the NSAIDs are generally equal in their analgesic effect if equipotent doses are used. The antiinflammatory effects may differ from patient to patient, so you may find that your patients respond to the various NSAIDs differently.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs) NSAID Generic Name (Brand Name) Salicylates (acetylated and nonacetylated) Aspirin, enteric-coated Salsalate (Disalcid) Diflunisal (Dolobid) Magnesium choline salicylate (Trilisate) Propionic acid derivatives Fenoprofen (Nalfon) Flurbiprofen (Ansaid) Ibuprofen (Motrin) Ketoprofen (Orudis, Orudis ER) Naproxen (Naprosyn) Naproxen sodium (Anaprox) Oxaproxin (Daypro) Acetic acid derivatives Diclofenac (Voltaren, Voltaren XR) Etodolac (Lodine, Lodine XL) Indomethacin (Indocin, Indocin SR) Ketorolac (Toradol) Nabumetone (Relafen) Sulindac (Clinoril) Tolmetin (Tolectin) Anthranilic acids Meclofenamate sodium (Meclomen) Oxicam derivatives Piroxicam (Feldene) Meloxicam (Mobic) COX-2 inhibitors Celecoxib (Celebrex)
Pathophysiology Various models and theories have been proposed to explain the genesis of anxiety disorders. Several neurotransmitter systems are involved in anxiety: (p. 617-625).
Noradrenergic: The autonomic nervous system produces norepinephrine. Excess amounts of norepinephrine can lead to tremulousness, palpitations, and hyperventilation The locus ceruleus (LC) in the brainstem contains 70% of the noradrenergic neurons in the brain and it releases norepinephrine in response to stress. Some of the drugs that are used to treat anxiety, such as tricyclic antidepressants and benzodiazepines, decrease neuronal firing in the locus ceruleus. GABA: Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter. When GABA interacts with a cellular receptor it causes chloride channels to open thus decreasing the ability of neurons to fire. Benzodiazepines enhance the action of GABA. Serotonin (5-HT): 5-HT1 receptors - stimulation of receptors is associated with antidepressant and anxiolytic effects 5-HT2 receptors - stimulation of receptors is associated with nervousness, insomnia, and sexual dysfunction 5-HT3 receptors - stimulation of receptors is associated with nausea and headache.
The SNRIs inhibit both norepinephrine and serotonin reuptake. In addition to the adverse effects noted with SSRIs as listed above, the unique potential adverse effect with this class is a dose-related hypertension. Patients should have their blood pressure monitored regularly; avoid this class of drugs in patients with pre-existing hypertension. Drugs in the class: Venlafaxine (Effexor) Desvenlafaxine (Pristiq) Duloxetine (Cymbalta) Milnacipran (Savella) - Milnacipran is a SNRI that is labeled and marketed for use as a treatment for fibromylagia. It is not labeled for use in depression. Levomilnacipran (Fetzima) - similar to milnacipran but is labeled for use in depression.
Norepinephrine/Dopamine reuptake inhibitor Bupropion (Wellbutrin) Bupropion inhibits dopamine reuptake and is a weak serotonin and norepinephrine re-uptake inhibitor. It has few anticholinergic, no sedative side effects, and causes little sexual dysfunction. It can cause insomnia and agitation. It can also lower the seizure threshold which is of most concern in the patient with a pre-existing seizure disorder. Bupropion is also sold as the brand name Zyban as a smoking cessation aid.
Opioids in Obstetrics
Opioid analgesics have a long history of use to relieve perinatal pain. Lipohilic opioids such as fentanyl and sufentanil traverse the placental membrane faster than the more hydrophilic opioids such as morphine. However, all opioids readily pass through the placental membrane and will reach the fetus. Administration of large doses of opioids to the mother can lead to neonatal respiratory depression, decreased alertness, and a delay in effective feeding. If opioids are to be used during labor, it is recommended that fentanyl, morphine, or hydromorphone be chosen. Meperidine is not recommended because the metabolite normeperidine may accumulate in the fetus/neonate, and leads to an increased risk of respiratory depression. Buprenorphine is not recommended because it is a partial agonist and it's actions are not readily reversed by naloxone. If opioids are used to treat chronic pain in the pregnant woman, the neonate should be observed and treated (if it occurs) for opioid withdrawal symptoms. Assessing and treating pain does not necessarily mean that opioid analgesics need to be used, particularly in the setting of persistent, non-cancer pain (see below for a discussion of the use of opioids in chronic, non-cancer pain).
There are three opioid receptors in the CNS and peripheral tissues: Mu receptors- are located primarily in pain-modulating areas of the CNS and induce central analgesia and respiratory depression. These receptors are responsible for the habituating and withdrawal effects of the opioids. Kappa receptors- are responsible for analgesia at the levels of the spinal cord and the brain. They appear to produce analgesia without inducing habituation. Delta receptors- are located in the limbic area of the brain and in the spinal cord and may play a role in the euphoria that the opioids produce.
Other receptors in pain Receptors Drugs Alpha-2 Clonidine Alpha and Beta receptors Norepinephrine Serotonin Tricyclic antidepressants, Sumatriptan GABA-B receptors Baclofen
Chronic Malignant Pain
Pain associated with malignancy can have nociceptive elements (e.g. when tissue damage occurs from tumor infiltration) and neuropathic elements (e.g. nerve destruction from chemotherapy or radiation). Inadequately treated malignancy associated pain can lead to anxiety, depression, insomnia and decreased quality of life. The pain should be managed with a multidisciplinary approach with the goal being to alleviate and prevent the pain.
Neuropathic Pain
Pain caused by abnormal processing of sensory input from the peripheral or central nervous system. The pain is less responsive to nonopioid or opioid analgesics and may require the use of adjuvant central nervous system medications (e.g. tricyclic antidepressants, gabapentin). Neuropathic pain can be further divided into centrally generated pain and peripherally generated pain. Centrally generated pain can be caused by injury to the nervous system (e.g. phantom pain after an amputation), or can be caused by dysregulation of the autonomic nervous system (e.g. pain associated with reflex sympathetic dystrophy). Peripherally generated pain is pain felt along the distribution of a peripheral nerve or group of nerves (e.g. diabetic neuropathy, trigeminal neuralgia).
Nociceptive Pain
Pain caused by stimuli that damages normal tissue or has the potential to do so if prolonged. The pain usually is responsive to nonopioids or opioids. It can further be divided into somatic pain and visceral pain. Somatic pain arises from bones, joints, muscles, or skin and is usually aching or throbbing in nature and is well localized. Visceral pain arises from organs such as the GI tract and can be either well localized or more diffuse in nature.
Chronic Non Malignant Pain
Pain not associated with a malignant disease and lasting >6 months beyond the healing period is considered to be chronic non-malignant pain. A multidisciplinary approach that addresses effective drug therapy along with rehabilitation and psychosocial issues works best with chronic non-malignant pain.
Pain perception can be affected by peripheral and central sensitization
Peripheral nociceptors become more responsive with the repeated application of noxious stimuli. Continuous exposure to inflammatory mediators can also enhance the sensitivity of the nociceptors. The sensitized nociceptors can become responsive to weak stimuli, leading to hyperalgesia and allodynia. The process of sensitization is known as wind-up or central sensitization. The number and response of nociceptive neurons increase without any change of input to the spinal cord. The goal of pain therapy should be to reduce peripheral sensitization and wind-up by interrupting the pain process as soon as possible using multiple modalities if necessary.
aspirin and NSAID
Patients often take one aspirin daily for antiplatelet effects and then also take a NSAID for osteoarthritis or pain. The NSAIDs will bind to the platelet and block the binding of the aspirin, but because the NSAID binding is reversible, the platelet becomes active as the NSAID serum levels decrease with time. To prevent this, take the aspirin first thing in the day - it irreversibly binds platelets and then if an NSAID is needed for pain relief later in the day, it can be taken with little additional antiplatelet effect.
Patients with Coronary Artery Disease (CAD) can't use the common abortive therapies for migraines (triptans, ergotamines). Prophylatic beta-blockers will be especially helpful for these patients because the beta-blocker will treat both the CAD and prevent migraines.
Petasites (butterbur) is an herbal remedy that is listed as a Level A treatment option in the AHS/AAN guidelines. Feverfew is listed as a Level B option and Coenzyme Q10 (100 mg three times daily) as a Level C option
Pediatric Considerations in Assessment and Treatment of Pain
Prior to the 1980s, it was a perception that because of an immature nervous system, infants did not feel pain. It is now known that this is not true -- infants do experience pain and should receive analgesics when undergoing painful procedures. Preverbal children can not self report pain using the pain scales described above, so the clinician must infer pain. Behavioral indicators of pain include facial expression, crying, changes in sleeping and eating patterns. The infant in pain may show increases in heart rate, respiratory rate, blood pressure.
Non-steroidal antiinflammatory Drugs (NSAIDs) The non-steroidal antiinflammatory drugs (NSAIDs) inhibit cyclooxygenase, a critical enzyme in the synthesis of prostaglandins.This inhibition occurs in both the CNS and the peripheral tissues so these agents have antipyretic, analgesic, and anti-inflammatory actions. There are two isoforms of COX -- COX-1 and COX-2. COX-1 is found in the stomach, intestine, kidney, and platelets and is necessary for the maintenance of these organs. COX-2 is only present in areas of inflammation. The traditional NSAIDs inhibit both COX-1 and COX-2. Cox-2 selective agents (e.g. celecoxib) inhibit COX-2 selectively.
Prostaglandins: Mediate the inflammatory process Mediate the pain process by sensitizing nociceptors to the effects of pain substances such as bradykinins. Maintain blood flow in the kidney, when there is a decrease in circulatory volume. Protect the gastric mucosa by decreasing gastric acid and maintaining blood flow to intestinal mucosa.
CDC's Guideline for Prescribing Opioids for Chronic Pain
Recommendations from the guidelines include: Nonopioid therapy is preferred for treatment of chronic pain. Opioids should be used only when benefits for pain and function are expected to outweigh risks. Before starting opioids, clinicians should establish treatment goals with patients and consider how opioids will be discontinued if benefits do not outweigh risks. When opioids are used, clinicians should prescribe the lowest effective dosage, carefully reassess benefits and risks when considering increasing dosage to 50 morphine milligram equivalents or more per day, and avoid concurrent opioids and benzodiazepines whenever possible. Clinicians should evaluate benefits and harms of continued opioid therapy with patients every 3 months or more frequently and review prescription drug monitoring program data, when available, for high-risk combinations or dosages. For patients with opioid use disorder, clinicians should offer or arrange evidence-based treatment, such as medication-assisted treatment with buprenorphine or methadone.
Choosing a Triptan
SQ sumatriptan (Imitrex) provides quickest onset of action -- headache relief starts within 10 minutes. Also useful in patient with vomiting Nasal sumatriptan -- has a slightly longer onset of action. Useful in patients with vomiting Oral sumatriptan, rizatriptan, zolmitriptan -- have a 30-60 minute onset. Are best in patients without vomiting who don't have a quick onset headache. Oral naratriptan has a longer half life so may be useful in patients whose migraines recur within 24 hours
Monoamine Oxidase Inhibitors (MAOIs) The MAOIs are old drugs that provide a therapeutic alternative for the treatment of depression. They have many drug-drug and drug-food interactions and require good patient cooperation before their use. The MAOIs include: phenelzine (Nardil) tranylcypromine (Parnate) Mechanism of Action: The traditional MAOIs inhibit the enzyme (monoamine oxidase) MAO which breaks down neurotransmitters. They inhibit both MAO-A and MAO-B. There are two isoforms of MAO: MAO-A breaks down serotonin, norepinephrine, epinephrine, dopamine, and tyramine and MAO-B breaks down phenylalanine ,benzylamine, dopamine and tyramine.
Side effects: orthostatic hypotension weight gain sexual dysfunction phenelzine (Nardil)--hepatocellular damage Numerous drug and diet interactions Diet Interactions: MAO-A breaks down tyramine in the intestinal epithelium. When a patient has a taken an MAO - A inhibitor, an excessive amount of tyramine can be absorbed across the gut wall. Tyramine is a precursor to norepinephrine. Foods with high tyramine content are not permitted: Aged cheeses (Cheddar, bleu, Swiss, etc.), smoked or pickled meats, aged/fermented meats (pate), Brewer's yeast, red wines If these food are eaten, you can see signs and symptoms of tyramine excess - hypertensive crisis--headache, stiff neck, nausea, vomiting, sweating, increased blood pressure. Occurs within 2 hours of ingestion of the food.
Clinical Presentation of Tension-Type Headache Tension headaches occur in 70-90% of the population Onset during adolescence or young adulthood is common Family history of headaches is common Only patients with more severe or chronic headaches seek medical attention
Signs and Symptoms of Tension-Type Headaches Mild-moderate intensity headache Tightening quality of headache - constriction, vise-like pressure Pain is bilateral and nonpulsating Duration of headache - 30 min to 1 week (average 12 hours) Not associated with vomiting
Clinical Presentation of Migraine Headaches 20 % of population may have migraines The prevalence of migraine is greater in women than in men Usual age of onset: 15 to 35 years Family history of migraine is common
Signs and Symptoms of a migraine Prodromal Symptoms (occur in up to 60%). These symptoms begin hours to days before the headache appears. Mental changes - either fatigue and drowsiness or irritability, hyperactivity Neurologic - photophobia, phonophobia General - sluggishness, thirst, anorexia, diarrhea or constipation The Aura (only occurs in 20% of patients with migraine). Aura usually precedes headache by 10 min. to 1 hour visual disturbances - blurred cloudy vision, scotomata, flashes of light vertigo transient aphasia photophobia pallor thick speech chills, tremor unilateral numbness The Headache Severe, throbbing headache - unilateral at first but later may spread to other side nausea and vomiting in 90% photophobia vertigo diarrhea tremors, chills, excessive perspiration Post Headache Skull on side of attack remains tender Patient may feel exhausted
Benzodiazepines Drugs in the Class: Chlordiazepoxide (Librium) Diazepam (Valium) Flurazepam (Dalmane) Clorazepate (Tranxene) Clonazepam (Clonopin) Prazepam (Centrax) Quazepam (Doral) Estazolam (Prosom) Oxazepam (Serax) Lorazepam (Ativan) Temazepam (Restoril) Alprazolam (Xanax) Triazolam (Halcion) Midazolam (Versed)
The benzodiazepines enhance the inhibitory actions of gamma-aminobutyric acid (GABA) in the central nervous system Benzodiazepines bind to benzodiazepine receptor thus enhancing GABA-receptor binding. GABA causes the chloride-ion channel in neuron to open, which stabilizes the cell membrane and decreases neuronal firing.
Midrin (Isometheptene, acetaminophen and dichloralphenazone) Midrin is a combination product that was used for many years in the treatment of migraines. The isometheptene acts on serotonin receptors, the acetaminophen is an analgesic, and dichloralphenazone is a mild sedative.
The clinical efficacy of Midrin is in question and there are few studies indicating effectiveness. The brand name Midrin is no longer marketed in the US but a generic form is available; the generic is expensive ($600/100 tabs) Adverse effects - are similar to ergotamine, but severe adverse effects are less likely to occur. Contraindications - same as with ergotamine
SSRIs with serotonin receptor activity
Vilazadone (Viibryd) - inhibits serotonin reuptake and activates serotonin1A receptors Vortioxetine (Trintellix) - inhibits serotonin reuptake and also activates serotonin1A and serotonin1B receptors; blocks serotonin3 and serotonin7 receptors. Adverse effects - similar to the SSRIs Clinical Use: Alternative agents to SSRIs; the additional activity at the serotonin receptors may give efficacy in some patients with difficult to treat depression.
Pathophysiology of Pain (p. 521-526)
Transduction: Nociceptors are exposed to mechanical, chemical, or thermal noxious stimuli. Inflammatory mediators such as histamine, bradykinins, and prostaglandin also stimulate the nociceptors. Electrical signals are generated at the peripheral receptor sites Transmission: The electrical signals are propagated along the neural membrane and are transmitted from the periphery to the spinal cord along two different nerve types. Myelinated A-fibers rapidly conduct impulses to the dorsal horn of the spinal cord and result in sharp or stabbing sensations. Unmyelinated C-fibers conduct electrical impulses at a much slower rate and result in pain that is dull, aching, and poorly localized. From the dorsal horn, neurons carry pain impulses to the thalamus and then the pain impulses travel from the thalamus to the central cortex of the brain. Modulation: Neurons originating in the thalamus and brain stem descend to the spinal cord and release inhibitory neurotransmitters such as norepinephrine, serotonin, and endogenous opioids to modulate or block the transmission of pain sensations. Perception: The conscious awareness of pain occurs and involves not only the nociceptive processes but the physiologic and emotional responses to the pain.
Acetaminophen
Toxicity: After it is absorbed, 90% of acetaminophen is metabolized by liver to non-toxic glucuronide and sulfate metabolites which are excreted in the kidneys. 10 % is metabolized by the cytochrome P-450 system to a potentially hepatoxic metabolite. Normally this metabolite combines with glutathione to form non-toxic mercapturic acid which is excreted in the kidney. When a toxic dose of acetaminophen is ingested, the glutathione is depleted and a toxic metabolite accumulates, causing hepatic cell death and liver failure. The full extent of the liver damage is not apparent until 2-4 days after the ingestion of the acetaminophen. Acetaminophen toxicity can be prevented by giving N-acetylcysteine (Mucomyst), which provides a source of glutathione. The respiratory form of the drug can be given orally; there is also an intravenous preparation that can be used. It must be given soon after the overdose (within 10-12 hours of the ingestion is best). Patients at higher risk for toxicity: alcoholics (patients who regularly drink alcohol (> 3 drinks per day), should limit their use of acetaminophen to 2 gm/day or less) Acetaminophen toxicity can occur with a surprisingly few tablets -- 7 grams of acetaminophen is only 14 extra-strength Tylenol tablets. In children, > 150 mg/kg is considered to be toxic. Once the signs and symptoms of liver dysfunction appear, it is too late to treat the toxicity -- so, this is one poisoning where you should have a high index of suspicion early; check serum levels and treat if necessary. It is not appropriate to wait for symptoms to appear.
Herbal Medications Note:
Two herbal medications that have been used for osteoarthritic pain are Boswellia serratia and Avocado-soybean unsaponifiables (Piasclidine). Both are oral medications and a Cochrane review reports that both have been shown to lower pain scores as compared to placebo, at least over the short term.
