Pharmacology of Pain Management
Leanne Drehmer
Pharmacology of Pain Management
Numerous classes of medications are available for the treatment of pain, and the treatment can be tailored depending on the nature and severity of pain (i.e., acute pain, chronic pain, and neuropathic pain).
An effective choice of medication for treating pain should include consideration of:
Allergies or sensitivities to medications.
Recent or previous history of pain medication used (what worked, what has not worked, and why).
Formulations of medications available (i.e., oral liquids, oral tablets, sustained-release oral tablets, injectables, and topicals).
Appropriate dosing, dose conversions, and relative potency.
Ineffective management of acute pain can not only lead to patient/caregiver dissatisfaction, but also may potentially lead to progression to chronic pain.
Classes of medications used for the management of pain include:
Non-opioid analgesics.
Opioid analgesics.
Co-analgesics/adjunctive agents.
Topical anesthetics.
Non-opioid Medications
Non-opioid medications are used for the treatment of mild to moderate pain.
The most common non-opioids are acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs).
Acetaminophen
Acetaminophen is a non-opioid analgesic that also has antipyretic properties, used for mild to moderate pain, and for fever.
Acetaminophen inhibits synthesis of prostaglandins in the central nervous system (CNS), and inhibits peripheral pain signal neurotransmission.
As an antipyretic, acetaminophen acts on the heat-regulating center in the hypothalamus, inducing vasodilation and sweating to disperse body heat.
Routes: oral (PO) or rectal (PR).
Dosing:
PO: 10–15 mg/kg/dose q4h PRN.
PR: 10–20 mg/kg/dose q4h PRN.
Onset: PO – 15 minutes, PR – 30 minutes.
Peak effect: PO – 30–60 minutes, PR – 2 hours.
Duration: PO/PR – 4–6 hours.
Pharmacokinetics:
Well absorbed orally, slower absorption and effect rectally.
Metabolized in liver via glucuronidation, and by P450 enzyme CYP2E1 to metabolite NAPQI (hepatotoxic in acute overdose).
Excreted by the kidneys.
Contraindications:
Liver dysfunction, hypersensitivity to acetaminophen.
Significant drug interactions:
Phenytoin, barbiturates (i.e., phenobarbital), and carbamazepine may decrease the levels and effect of acetaminophen.
Minor increase in bleeding risk with warfarin.
Adverse effects:
Nausea/vomiting (may take with food).
Rash.
Hepatotoxicity with chronic use or acute overdose.
Renal injury with chronic use.
Monitoring:
Pain and/or fever reduction, liver enzymes and liver function tests (LFTs) with chronic use.
Acetaminophen special considerations and pearls:
Lack of action on prostaglandins in the peripheral nervous system (PNS) likely related to lack of anti-inflammatory action.
No gastric irritation/ulceration compared to NSAIDs.
Extended-release 650-mg tablets also available, but usually not used for acute pain in children.
Caution different concentrations of oral drops (80 mg/mL) versus oral liquid suspension (32 mg/mL).
Be aware that acetaminophen is a component of multiple over-the-counter and prescription products, limit acetaminophen content from all sources to ≤75 mg/kg/day.
Ensure that the foil is removed from suppositories prior to insertion; half doses should be achieved by cutting suppositories lengthwise symmetrically.
PR absorption is slower and less complete than oral absorption (see dosing above).
Oral liquid may be instilled rectally (limit volume to 80 mg/1 mL).
Nonsteroidal Anti-inflammatory Drugs
NSAIDs are used for treatment of mild to moderate pain.
NSAIDs inhibit the peripheral synthesis of inflammatory prostaglandins, and have analgesic, anti-inflammatory, and anti-pyretic properties.
Typical NSAIDs used in the pediatric population are ibuprofen, naproxen, and ketorolac.
Routes: PO, PR; IM/IV (ketorolac).
Dosing:
Ibuprofen: PO – 5–10 mg/kg/dose PO q6–8h.
Naproxen: PO – 5–10 mg/kg/dose PR BID PRN.
Rectal dosing: less than 50 kg–250 mg/dose PR, greater than 50 kg–500 mg/dose PR (maximum 1,000 mg/day).
Ketorolac: IV/IM/PO 0.5 mg/kg/dose q6h PRN (see special considerations below; maximum 15–30 mg/dose).
Administer PO with food to decrease stomach irritation.
Onset: PO – 30–60 minutes, PR – 2 hours, IM/IV – 30 minutes.
Peak effect: PO – 2–4 hours, PR – 4 hours, IM/IV – 2–3 hours.
Duration – PO/PR/IM/IV – 6–8 hours.
Pharmacokinetics:
Well absorbed orally, slower absorption rectally.
Metabolized by liver, eliminated by kidneys.
Contraindications:
Hypersensitivity to NSAIDs.
Severe asthma triggered by NSAID use.
Acute active bleeding.
Elevated bleeding risk.
Significant drug interactions:
Anti-platelet agents, anticoagulants, steroids (ASA, clopidogrel, warfarin, prednisone, etc. – additive bleeding risk).
Anti-hypertensive medications (ACE inhibitors, B-blockers – reduced anti-hypertensive effect).
ACE inhibitors, diuretics (increased risk of hyperkalemia).
NSAIDs may increase the levels of aminoglycosides (i.e., gentamicin), cyclosporine, digoxin, haloperidol, lithium, methotrexate, quinolones (i.e., ciprofloxacin), and vancomycin.
Levels and effects of NSAIDs may be increased by tricyclic antidepressants (i.e., amitriptyline), selective serotonin reuptake inhibitors (SSRIs) (i.e., fluoxetine), serotonin/norepinephrine reuptake inhibitors (SNRIs) (i.e., venlafaxine), and probenecid.
Adverse effects:
GI irritation/nausea/vomiting/heartburn (take with food).
Rash and pruritus.
Dizziness.
Fluid retention.
Monitoring:
Reduction of pain/fever/inflammation.
Blood pressure/edema for cardiac patients.
Liver enzymes/LFTs, CBC, and renal function for chronic use.
NSAID special considerations and pearls:
Relative increasing potency of NSAIDs generally ibuprofen → naproxen → ketorolac.
Naproxen helpful in rheumatic or inflammatory disorders.
Ketorolac to be used parenterally IV or IM if patient not able to tolerate other PO NSAIDs, and to be used short term only (i.e., <5 days) due to GI irritation/bleeding risk. The IM route is also painful.
May transition to PO ketorolac if needed, but preferred to use ibuprofen as PO agent.
Opioid Medications
Codeine
Codeine is an opioid analgesic inhibiting neurotransmission in the ascending pain pathway, and an antitussive (in lower doses), acting centrally on the medulla.
Codeine is a pro-drug, which does not have significant pharmacological activity until metabolized by cytochrome P450 CYP2D6 enzymes in the liver to the active metabolite, morphine (∼10% metabolized to active morphine).
Codeine should be used with caution for pediatric pain management due to variable pharmacokinetics and unpredictable efficacy and toxicity.
Routes of administration: PO, IM, subcutaneous (Subcut).
Dosing:
PO analgesia: 0.5–1 mg/kg/dose q4–6h PRN.
PO antitussive: 0.15–0.3 mg/kg/dose q4–6h PRN.
IM/Subcut: 0.5–1 mg/kg/dose q4–6h PRN.
Maximum analgesic dose: 1.5 mg/kg/dose, or 60 mg/dose.
Maximum antitussive dose: 20 mg/dose.
Adjust dose for renal impairment.
Sustained-release products used for chronic pain and dosed based on average daily requirements of immediate-release preparations, usually dosed q12h.
Product availability and administration:
PO liquid: codeine phosphate – 5 mg/mL.
PO immediate-release tablets: codeine phosphate – 15 and 30 mg.
PO sustained-release tablets (for chronic pain): codeine contin (codeine sulfate trihydrate) – 50, 100, 150, and 200 mg.
IM/Subcut: 30 mg/mL ampoule q4–6h PRN.
IM or Subcut no dilution required, do not administer IV.
Onset: PO – 30–60 minutes; IM/Subcut – 10–30 minutes.
Peak effect: PO – 60–90 minutes (4 hours for sustained release); IM/Subcut – 30–60 minutes.
Duration: PO and IM/Subcut – 4–6 hours (12 hr for sustained-release PO tablets).
Pharmacokinetics:
Readily absorbed orally, ∼60% bioavailability (see Section IV: PO Conversion, Table 10.3).
Low protein binding.
Metabolized by CYP2D6 in liver into morphine-active metabolite.
Eliminated primarily by the kidneys.
Contraindications:
Hypersensitivity/allergy to codeine or morphine.
Significant drug interactions:
Other CNS depressant/respiratory depressant medications (i.e., other opioids and benzodiazepines).
Quinidine (inhibits CYP2D6, decreased effect of codeine).
Adverse effects:
Excessive sedation.
Respiratory depression.
Bradycardia.
Hypotension.
Dizziness.
Drowsiness.
Constipation.
Urinary retention.
GI upset (may take with food).
Monitoring:
HR, RR, BP, reduction in pain score, level of sedation and constipation.
Codeine special considerations and pearls:
Respiratory depression can occur even at therapeutic doses (not necessarily only at toxic doses).
Codeine does not necessarily have less adverse effects than stronger opioids.
Genetic polymorphism – variable pharmacokinetics and unpredictability.
P450 CYP2D6 enzyme that metabolizes codeine to morphine for therapeutic effect is highly polymorphic.
Up to 28% of North African, Ethiopian, or Saudi Arabian patients; 10% of Caucasian patients; 3% of African American patients, and 1% of Chinese, Japanese, or Hispanic patients are “ultra-metabolizers” – meaning more than expected codeine is metabolized to morphine (excessive sedation, respiratory depression, or even death may result).
“Slow or poor metabolizers,” on the other hand, may experience ineffective pain relief with codeine.
Genetic testing for CYP2D6 polymorphism is not readily commercially available, thus it is preferential to prescribe oral or parenteral morphine directly (rather than producing morphine indirectly through codeine metabolism).
IV administration of codeine is not recommended due to significant histamine release and potential for severe vasodilation, hypotension, and cardiac/respiratory arrest.
IM/Subcut administration of codeine is also not recommended as painful and poorly tolerated.
Multiple combination products containing codeine are available; be aware of potential for additive sources of codeine.
Prescribed in mg, not mL for oral liquids.
Do not crush sustained-release products used for chronic pain.
Consider stool softener or mild laxative to mitigate constipation.
Morphine
Morphine binds to the μ-opioid receptors in the CNS, inhibiting neurotransmission in the ascending pain pathway.
Routes of administration: PO, IV, IM/Subcut, and PR.
Dosing:
Intermittent parenteral doses: 0.05–0.1 mg/kg/dose IV/IM/Subcut q2h PRN.
Intermittent oral/rectal doses: 0.2–0.5 mg/kg/dose PO/PR q4h PRN.
Continuous infusion: 0.1 mg/kg IV bolus loading dose, then 10–40 mcg/kg/hr IV/Subcut infusion, with 0.1 mg/kg/dose q1h PRN for breakthrough pain.
Sustained-release products used for chronic pain and dosed based on average daily requirements of immediate-release preparations.
Adjust dose in renal impairment.
Product availability and administration:
PO liquid: morphine – 1 mg/mL.
PO immediate-release tablets: 5, 10, 20, 25, 30, 40, 50, and 60 mg.
PO q12h sustained-release tablets (MS-Contin): 15, 30, 60, and 100 mg
PO q24h sustained-release capsules (Kadian): 10, 20, 50, and 100 mg.
PO extended-release capsules (M-Eslon): 15, 30, 60, and 100 mg.
Suppository: 5, 10, 20, and 30 mg.
Injectable: 2, 10, and 50 mg/mL.
Inject slowly over 2 minutes, dilute with NS or D5W to a maximum concentration of 5 mg/mL (rapid IV administration may produce excessive histamine release, hypotension, respiratory/cardiac depression). Ensure respiratory support is readily available.
Wean continuous infusions slowly to prevent withdrawal syndrome.
For chronic pain, sustained-release capsules may be opened and sprinkled on food (pellets to be swallowed whole).
Onset: PO/PR – 30 minutes (60 minutes for controlled-release PO preparations); IV/IM/Subcut: 5 minutes.
Peak effect: PO/PR – 60 minutes (∼4 hr for controlled-release PO preparations); IV/IM/Subcut – 10–20 minutes.
Duration: PO/PR – 4 hours (12 hr for controlled-release PO preparations); IV/IM/Subcut – 3–4 hours.
Pharmacokinetics:
Good oral absorption, bioavailability ∼40% (see Section IV: PO conversion section, Table 10.3).
Moderate protein binding.
Morphine is the active metabolite of codeine (via CYP2D6), and also produces active metabolite (morphine-6-glucuronide) when morphine is metabolized in the liver by glucuronidation (does not involve P450 CYP enzymes).
Eliminated primarily by the kidneys.
Contraindications:
Hypersensitivity/allergy to morphine or codeine.
Significant drug interactions:
Other CNS depressant/respiratory depressant medications (i.e., other opioids, benzodiazepines).
Morphine may increase levels of SSRIs, thiazide diuretics.
Succinylcholine, amphetamines, and antipsychotics may increase the levels/effects of morphine.
MAO inhibitors may increase the effect of morphine.
Adverse effects:
Excessive sedation.
Respiratory depression.
Bradycardia.
Hypotension.
Dizziness.
Drowsiness.
Pruritus.
Constipation.
Urinary retention.
GI upset (may take PO with food).
Monitoring:
HR, RR, BP, oxygen saturation, reduction in pain score, level of sedation, and constipation.
Morphine special considerations and pearls:
Preservative-free morphine is available for epidural or intrathecal use.
High-alert medication for medication errors associated with abbreviations – not to be prescribed as MSO4 for morphine sulfate (interchange error with magnesium sulfate – MgSO4).
Prescribe in mg, not mL for oral liquid.
Do not crush sustained-release products for chronic pain.
Consider stool softener or mild laxative to mitigate constipation.
Fentanyl
Synthetic opioid analgesic (increased potency compared to morphine), which is short acting.
Binds to μ-opioid receptors in CNS to inhibit ascending pain pathways.
It has sedative and analgesic properties.
Routes of administration: IV/IM/Subcut, intranasal, and topical patch.
Dosing:
IV/IM/Subcut intermittent: 0.5–1 mcg/kg/dose q1h PRN.
IV continuous infusion: 1–2 mcg/kg bolus, then 0.5–3 mcg/kg/hr, with 1–2 mcg/kg/dose q1h PRN for breakthrough pain.Related posts:
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