Pharmacologic therapy can be either curative or palliative. Relief of cardiac chest pain by the vasodilatory effect of nitroglycerin is an example of curative therapy. This chapter deals primarily with palliative therapy; once a diagnosis has been established, curative therapy is preferred over palliation alone if possible.
Non-opioid agents
Non-opioid agents are listed in Table 8.4.
Acetaminophen
Acetaminophen is an effective analgesic for mild to moderate pain. Its mechanism of action is
unclear, yet it seems to act centrally.
Acetaminophen has little anti-inflammatory effect and few gastrointestinal side effects. It does not affect platelet aggregation. Significant hepato- toxicity is known to occur with large overdoses.
Non-steroidal anti-inflammatory drugs The mechanism of action of NSAIDs is thought to be due to inhibition of prostaglandin, and possibly leukotriene production. Alone, prostaglandins do not cause pain, but sensitize nerve endings to perceive an ordinary, non-painful stimulus as painful. NSAIDs are widely used for their antipyretic and anti-inflammatory properties, in addition to their analgesic properties. They are effective for mild to moderate pain, and their lack of respiratory depression and abuse poten- tial makes them an attractive choice. There is a
“ceiling effect” beyond which no further analge- sia can be produced, even when a different NSAID is added. Their major side effects include
Pain management
Table 8.3 Analgesic modalities and their mechanisms of action
Distraction Cognitive focus away from pain Music Cognitive focus away from pain
and decreased anxiety Hypnosis Cognitive reinterpretation of
painful stimuli
Biofeedback Decreases muscle tension Placebo Activates descending pain inhibitory
pathways. May involve endorphins TENS Interferes with transmission in
dorsal horn ganglia. Possibly stimulates endorphins Acupuncture Probably similar to TENS Local Blocks transmission of afferent anesthesia nerve impulses
NSAIDs Block production of prostaglandins Opioids Bind to opiate receptors in
central nervous system (CNS) and possibly in peripheral nerves Nitrous oxide Blunts emotional reaction to pain;
possible role of endogenous opioids
NSAIDs: non-steroidal anti-inflammatory drugs;
TENS: transcutaneous electrical nerve stimulation.
gastrointestinal bleeding, renal failure, anaphy- laxis, and platelet dysfunction. The same anal- gesics that are effective in adults can be safely administered to children greater than 2 months of age. In children, the margin of safety of these drugs approximately equals that in adults.
Aspirin
Aspirin may cause Reye’s syndrome in children who contract influenza or chickenpox. Aspirin is
now seldom used in children, except to treat autoimmune diseases such as juvenile rheuma- toid arthritis.
Ketorolac tromethamine
Ketorolac is the first non-opioid analgesic agent available for parenteral use in the US. For acute musculoskeletal pain, 60 mg ketorolac administered IM has been shown approximately
Pain management
Table 8.4 Non-opioid analgesics
Generic Dose Pediatric dose Toxic dose Maximum dose
(proprietary)
Acetaminophen 650–1000 mg PO 10–20 mg/kg PO Not an NSAID. Exact mechanism 100 mg/kg/day (APAP) q4–6 h 20–40 mg/kg PR q4 h unknown. Liver toxicity possible
1 g PR q6 h when above 150 mg/kg is taken
1–2 g PR q12 h in 24 hour
Aspirin (ASA) 650–975 mg PO q4 h 10–15 mg/kg PO Reye’s syndrome in children who 60 mg/kg/day subsequently get flu or chickenpox.
Tinnitus
Toxic dose 150 mg/kg
Ibuprofen 600 mg PO q6–8 h 10 mg/kg PO q6–8 h GI irritation 40 mg/kg/day
Platelet dysfunction Renal dysfunction Bronchospasm
Naproxen 250 mg PO q6–8 h 5–7 mg/kg PO q12 h Interacts with protein-bound drugs 20 mg/kg/day 500–100 PR q12 h
Indomethacin 25–50 mg PO q12 h N/A As for naproxen 3 mg/kg/day
100 mg PR q24 h
Ketorolac 60 mg IM/dose 0.5 mg/kg IV q6 h Same as IB. Decrease dose by 30 mg IV/dose Max 120 mg/d one-half in elderly.
Rofecoxib 12.5–50 mg PO qd Available as liquid Selective COX-2 inhibitor. Withdrawn
(Vioxx) due to increased risk of serious
cardiovascular events
Celecoxib 200 PO bid Not approved Not available as liquid; contraindicated in sulfa allergy. May increase risk of serious cardiovascular events Valdecoxib 10 mg PO qd Not approved No renal elimination; should not
be given to sulfa-allergic patients.
May increase risk of serious cardiovascular events
Tramadol 50–100 mg PO Not approved May precipitate serotonin syndrome in SSRI patients (no actual pediatric indications, but studies support safety and efficacy in children)
COX: cyclooxygenase; GI: gastrointestinal; IB: ibuprofen; IM: intramuscular; IV: intravenous; NSAID: non-steroidal anti-inflammatory drug; PO: per os; PR: per rectum; SSRI: selective serotonin reuptake inhibitors.
equivalent in analgesic efficacy to 800 mg of oral ibuprofen. Ketorolac inhibits prostaglandin syn- thesis, so its onset is no faster than that of an equivalent agent given orally. Ketorolac is con- sidered to be most useful in the context of renal colic because decreased prostaglandin synthesis results in decreased ureteral peristalsis. In the- ory, opioids increase smooth muscle spasm and peristalsis; nonetheless, opioids have proven to be effective analgesics in renal colic and should be considered as standard therapy. Ketorolac is approximately 10–35 times more expensive than morphine.
Cyclooxygenase-2 specific inhibitors
Cyclooxygenase-1 (COX-1) serves as a “clean-up”
or reparative agent and is not inducible with stimu- lation from inflammation or injury. COX-2 is pres- ent in lower levels and is inducible, showing increases that are closely related to the inflamma- tory response to injury or inflammation. Most traditional NSAIDs block both COX-1 and COX-2.
The selective COX-2 inhibitors rofecoxib and celecoxib provide anti-inflammatory effects and moderate analgesia with a lower incidence of gas- trointestinal side effects. Both are eliminated by the liver, and share similar drug interactions with standard NSAIDs. They may precipitate anaphyl- axis in patients with aspirin allergy. Celecoxib is metabolized by the cytochrome P450 system and may cross-react in patients who have a sulfona- mide allergy. Rofecoxib (Vioxx) has been taken off the market because of its association with an increased incidence of myocardial infarction.
General guidelines for choosing non-opioid analgesic agents 1. Use cautiously in the elderly, who are at
greater risk of developing gastrointestinal bleeding, renal toxicity and renal failure.
2. Patients who are dehydrated or
hypovolemic are at high risk of acute renal impairment.
3. All have the potential for gastrointestinal side effects.
4. They may interfere with the effects of many antihypertensives.
5. There is little clinical evidence of individual superiority of one particular agent over another.
6. Newer agents may cost as much as fifty times more than older ones.
Opioid analgesic agents
Opioid analgesics are the mainstay of pharmaco- logic management of acute, moderate to severe pain (Table 8.5). The beneficial physiologic and psychologic effects of opium have been well docu- mented for centuries; so have its toxicity and potential for abuse. Fear of inducing addiction has led to the underuse of opioids by many physicians. However, many studies have shown that short-term use of opioid analgesics for acute pain syndromes is not associated with future dependence.
There are multiple opioid receptors, each affected by opioids in different ways. The most commonly used opioids are -agonists: mor- phine, meperidine, methadone, codeine, oxy- codone, and the fentanyls. An agonist acts as a neurotransmitter – when the receptor recognizes the agonist, it causes alterations within the cell.
An antagonist blocks the receptor by occupying it without initiating transduction. Partial agonists produce a partial response with decreased intrin- sic activity. By binding the receptor site, they also block access of full agonists and function as par- tial antagonists.
Morphine
Morphine is the gold standard opioid agent. In standard dosage, it produces analgesia without loss of consciousness. Relief of tension, anxiety, and pain then results in drowsiness and sleep.
Nausea, vomiting, pruritus, and miosis are the most common side effects. Vasodilatation and venous pooling from morphine do not cause sig- nificant hemodynamic effects in normovolemic patients, but can cause significant hypotension in hypovolemic patients. Morphine causes dose- dependent depression of ventilation, reducing the respiratory rate and then tidal volume. Morphine increases sphincter tone at the pylorus, ileo-cecal junction, and the sphincter of Oddi, and decreases peristalsis, resulting in constipation.
Fentanyl
Fentanyl’s advantages over morphine include a rapid onset (1 minute) and brief duration of action (30–45 minutes). It is 50–100 times more potent than morphine and has little hypnotic or sedative effect. Fentanyl’s main disadvantage is the glottic and chest wall rigidity that may develop after rapid infusion of higher doses
Pain management
(5 mcg/kg). The mechanism of the “rigid chest”
syndrome is unclear, but can be life-threatening, since assisted ventilation may be impossible with- out muscle relaxants.
Hydromorphone
Hydromorphone is a derivative of morphine, and has greater selectivity for -opioid receptors.
It has a rapid onset of action and lasts 4–6 hours.
Hydromorphone is five times more potent and ten times more lipid soluble than morphine, yet less sedating. It also produces less nausea.
Opioid drug selection
The idea that some opioids are weak and inef- fective in severe pain is outdated. In equipotent
doses, opioid agents can achieve the same effect as other opioids, but differ in their side effects and half-life. Factors affecting drug selection include:
the intensity of the pain, coexisting disease, poten- tial drug interactions, treatment history, physician preference, patient preference, and proposed route of administration.
Choice of route of administration Injectable
The IV route results in the shortest time to onset of pain relief. There is no “maximal” dose of opi- oid; induction of undesired side effects usually signals the limit of the patient’s ability to tolerate the drug. Patient-controlled analgesia (PCA) is commonly used in the inpatient setting for severe pain that is expected to last for hours or days. In general, PCA does not have a role in the
Pain management
Table 8.5 Opioid analgesics
Generic Oral equipotent Parenteral Duration Comments Precautions
(proprietary) dose (in hours)
Morphine 30–60 mg 10 mg 3–5 Standard for comparison Respiratory depression
(0.5 mg/kg) (0.1 mg/kg) Hypotension
Sedation Histamine release
Codeine 30–100 mg 30–100 mg 4 Poor analgesic Constipation, nausea
(2 mg/kg) (0.5 mg/kg) Good cough and vomiting, abuse
suppressant potential
Hydromorphone 2–6 mg 1–2 mg 2–4 Available as suppository Euphoria (Dilaudid) (0.02–0.1 mg/kg) (0.015 mg/kg)
Hydrocodone 5–10 mg N/A 3–4 Good cough Greater abuse
(Vicodin, Lortab) suppressant potential
Fewer side effects than codeine and greater potency
Oxycodone 5–10 mg N/A 3 Parenteral form not Euphoria, abuse
(Percocet, Tylox) available in the US. Very potential
effective analgesic
Meperidine 250–300 mg 75–125 mg 2–3 Toxicity from metabolite Avoid with MAOI.
(Demerol) (1.5–2.0 mg/kg) (1.0 mg/kg) normeperidine Caution in renal or hepatic failure Fentanyl N/A 0.1–0.2 mg 1–2 No histamine release. For IV administration,
(0.001 mg/kg) Transcutaneous and push and flush slowly transmucosal to avoid “rigid chest”
absorption syndrome
Alfentanil N/A 1 mg/kg 1.5 Shortest half-life, minimal Muscular rigidity if (0.01 mg/kg) cardiovascular side administered too
effects quickly; expensive
MAOI: monoamine oxidase inhibitor; IV: intravenous.
ED setting, but may be beneficial to patients in observation units or for those whose ED stay is prolonged due to lack of inpatient beds.
The IM route has multiple disadvantages.
Among them, the pain of the injection limits the physician’s ability to titrate the drug effect. Fur- thermore, drug uptake is variable, depending on the patient’s peripheral circulation.
Oral
First-pass hepatic metabolism may inactivate as much as 80% of an oral opioid dose. Patients who will require general anesthesia cannot take any- thing by mouth. Patients who are vomiting will not be able to retain the drug long enough for absorption to occur. Time to onset of analgesia is much longer and titration is more difficult. Out- patient pain control after discharge is the main reason to use oral opioids.
Rectal
The rectal route has the advantages of transmu- cosal absorption without the first-pass effect.
Additionally, it does not rely on gastric motility.
Absorption, however, is variable. Patients may object to this route of administration. Hydromor- phone is the only opioid available as a suppository.
The IV form can also be given rectally.
Transmucosal
Fentanyl lollipops are the most common form of opioid using the transmucosal route. This is espe- cially helpful in children, but requires patient cooperation.
Combination therapy
The combination of a non-opioid analgesic and an opioid agent produces significantly greater pain relief than either agent alone.
Use of adjuvant agents
Adjuvant agents are used in combination with opioids for various reasons: to provide synergy;
to decrease side effects; to decrease anxiety; and to relax muscles, especially in acute musculoskel- etal pain. The phenothiazines and hydroxyzine are most commonly used. There is no evidence, however, for analgesic synergy with these agents.
Phenothiazines do not potentiate analgesia, as previously believed, and may actually diminish the analgesic effect of the simultaneously admin- istered opioid. Hydroxyzine not only requires an additional injection, but also increases respiratory depression. In severe musculoskeletal pain associ- ated with muscle spasm, the addition of a muscle relaxant may provide more relief than an opioid alone. In this scenario, respiratory status must be monitored closely. In general, adjuvant agents provide little additional analgesia and may poten- tiate or add side effects to the clinical picture.
Special patients
Undifferentiated abdominal pain
Fear of masking the clinical findings and missing the diagnosis has long prevented physicians from giving opioids to patients with undifferen- tiated abdominal pain, leaving them to suffer for hours while establishing a diagnosis and definitive treatment. This practice was first promulgated by Cope, from his 1921 text The Early Diagnosis of Abdominal Pain. “If morphine be administered, it is possible to die happy in the belief that he is on the road to recovery, and in some cases, the med- ical attendant may for a time be induced to share the same delusive hope.” Newer diagnostic tech- niques, better monitoring, and more accurate opioid titration have made his dire warning obsolete. In fact, the most recent edition of Cope’s textbook retracts this myth. Several studies have documented that early pain relief in patients with acute abdominal pain is safe and does not result in worse outcomes, even in children.
Migraine headaches
There have been many studies comparing the effectiveness of non-opioid agents to opioids in the management of migraine headaches. The phenothiazines have shown success rates as high as 95%. Sumatriptan and dihydroergotamine have been associated with recurrence rates as high as 50%, especially in patients with persisting headache at the time of discharge from the ED.
Many other drugs (metoclopramide, haloperidol, droperidol, NSAIDs, and narcotics) have been studied. The relative benefit of any of these drugs or any combinations has not been established.
Opioids have not been shown to perform better in clinical trials and have the potential to be associ- ated with subsequent drug-seeking behavior.
Pain management
Chronic pain
The patient with a terminal illness and chronic pain should receive generous amounts of opioids while the physician searches for a new process that might have caused increased pain. These patients will have great tolerance for the anal- gesic effects of opioids, but not necessarily for their side effects. Patients who have chronic pain with a non-terminal illness should be under the care of a primary care provider who has a plan for managing this pain. Close consultation with that primary care provider, or the pain manage- ment team, if applicable, will optimize the patient’s care and reduce dependency and abuse.
Suspected drug-seeker
Some patients will feign pain or claim pain syn- drome diagnoses in order to receive opioids, either for their own use or to sell. Suspected drug-seeking behavior should be documented and will become evident as the number of ED visits increase. In general, it is better to err on the side of humane treatment than to deprive a patient of needed pain relief. Diligence in check- ing the history and physical for inconsistencies, communicating with the patient’s primary care provider, and checking the medical records will help identify drug seekers and drug-seeking behavior. Non-narcotic medications should be substituted when possible. Prescriptions should be written for only small amounts of medication, in matching alphabetic and numeric formats.
Communication between the primary care provider and ED personnel will serve not only to confirm the physician’s suspicions, but can also provide the basis for a consistent care plan for future visits. Documentation of findings and dis- cussions are necessary parts of the medical record.