March 2005 Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection Managing Complications of HIV Infection in HIV-Infected Children on Antiretroviral Therapy Pain Management

03/05 About This Presentation These slides were developed using the March 2005 Pediatric Guidelines. The intended audience is clinicians involved in the care of patients with HIV. The user is cautioned that, due to the rapidly changing field of HIV care, this information could become out of date quickly. Finally, it is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent. -AETC NRC

03/05 Introduction  Pain is multifactorial, biologically complex  Associated with decreased quality of life, increased mortality, lower CD4%  Common, particularly in younger children and girls  Sources: many, including nerve or muscle inflammation, cardiomyopathy, drug toxicities, invasive secondary infections  Stressors may amplify pain

03/05 Assessment  Self-report  Pediatric visual analogue pain scales and rating systems, modified for age, developmental status, severity of illness, cultural factors  Observational and behavioral assessment  Functional performance  General Health Assessment for Children  Functional Status II (R)

03/05 Principles of Pain Management  Diagnose and treat underlying medical conditions  Involve the child and caretakers in developing strategies  Consider consultation with pediatric pain specialist  Combine nonpharmacologic and pharmacologic therapies

03/05 Nonpharmacologic Interventions  Relaxation techniques, behavior modifications  Environmental management (play, music, scheduled medical/nursing interventions, structured sleep and rest times)  Gentle handling, supportive positioning  Nutritional support, hydration, electrolyte replacement  Optimized tissue perfusion and oxygenation  Transcutaneous electrical stimulation (TENS), massage, whirlpool, physical therapy  Acupuncture

03/05 Pharmacologic Treatment  Dosing guidelines should be consulted, but dosages must be individualized  Effective pediatric analgesic dosage may not be identified (eg, tricyclics, SSRIs, and anticonvulsant medications)  For adjunctive analgesics, analgesic dosage may be lower than the standard dosage for a medication’s primary indication  Start at low dosages, increase as necessary and as tolerated

03/05 Pharmacologic Treatment  Many analgesics undergo hepatic metabolism  May have interactions with PIs or NNRTIs  Analgesic and/or ARV drug levels may be altered  Risk of analgesic toxicity or withdrawal; suboptimal or toxic PI or NNRTI concentrations

03/05 Types of Medications Drug CategoryRepresentative Medications Comments GABA agonists Baclofen, midazolam, lorazepam, diazepam Baclofen is often used for muscle spasms; stimulates GABA-B receptors, inhibiting the release of the excitatory amino acids glutamate and aspartate. Mu opioid agonists Fentanyl, morphine Respiratory monitoring required. Transdermal fentanyl should not be used for episodic pain, as it has a slow onset, long duration. NMDA receptor antagonists Dextromethorphan, ketamine Dextromethorphan may cause ataxia, dizziness. Ketamine may increase heart rate, blood pressure, cardiac output, and intracranial and intraocular pressure; also may cause hallucinations. Mixed agonists Methadone (mu opioid and NMDA effects); tramadol (mu opioid and norepinephrine, serotonin effects) Methadone is available in liquid form for young children. Marked variability in clearance requires close monitoring to avoid excessive sedation. Pediatric dosage, safety, and duration of administration have yet to be determined for tramadol.

03/05 Types of Medications Drug CategoryRepresentative Medications Comments Alpha2 adrenergic agonist Clonidine Modulates sympathetic responses. Opioid-sparing effect. Transdermal dosing available. Discontinue if patient is hypotensive, septic, or depressed. Tricyclic antidepressants Amitriptyline, nortriptyline Blocks NMDA receptors. Releases endogenous opioids. Clearance is variable. Additional benefit with second (a.m.) dose. Plasma concentrations may guide high doses. SSRIs Paroxetine, sertraline, fluoxetine Mechanism of antinociceptive effect unknown; may involve both central opioid and serotoninergic pathways. Anticonvulsants with analgesic effect Gabapentin, lamotrigine, topiramate Gabapentin modulates calcium channels, increases GABA synthesis, reduces glutamate. Used in treatment of neuropathic pain. Topiramate: monitor for drug interactions with ARVs. NSAIDs Ibuprofen, celecoxib, diclofenac, acetaminophen, ketorolac Inhibits cyclooxygenase-2 (COX-2). Few class differences. Ketorolac is the primary parenteral NSAID, but may cause hepatic dysfunction and GI bleeding.

03/05 Special Considerations Opioids  For moderate to severe pain  Excellent analgesia; generally safe  Concurrent use with other agents may enhance analgesia:  GABA agonists, alpha2 agonists, TCAs, SSRIs, anticonvulsants

03/05 Special Considerations Opioid complications:  Excessive sedation  Consider low-dose a.m. stimulants (dextroamphetamine, methylphenidate)  Itching and constipation  Consider very small doses of naloxone  Switch narcotic (eg, to methadone)  Nausea and vomiting  Change narcotic

03/05 Special Considerations Methadone  Has NMDA receptor antagonism  Recommended for long-term treatment of neuropathic pain refractory to nonnarcotics  May induce less tolerance than other narcotics  In adults, may be associated with lower CD4%

03/05 Special Considerations Methadone Switching to methadone from high-dose morphine, Dilaudid, fentanyl  Incomplete cross-tolerance to methadone  Start at LOW dosage (20% of expected equipotent dosage)  Risk of respiratory depression at full equipotent dosage

03/05 Special Considerations Methadone  Some PIs (eg, lopinavir) and NNRTIs (efavirenz, nevirapine) induce metabolism of methadone, lower serum drug levels  Opioid withdrawal symptoms may occur  Higher methadone doses may be needed  Risk of methadone toxicity if interacting ARVs are discontinued

03/05 Special Considerations Weaning from long-term opioid and benzodiazepine therapy  Minimize physiological stress  Use clonidine (alpha2 agonist), transdermal or oral, to reduce withdrawal symptoms  Transition from IV narcotics to methadone (or fentanyl patch, morphine, MS Contin)  Transition from midazolam to lorazepam

03/05 Special Considerations Weaning from long-term opioid and benzodiazepine therapy  Wean methadone 5-10% every 2-3 days, as tolerated, alternating with 5-10% wean of lorazepam  Wean clonidine at least 3-5 days after discontinuation of narcotics  Assess frequently for withdrawal symptoms

03/05 Special Considerations Escalating narcotic and sedative requirements  Initiate alpha2 agonist and NMDA receptor antagonist  Consider clonidine, dextromethorphan (low- dose)  Substitute methadone for other narcotics, lorazepam for midazolam  Consider rotating narcotics  Consider regional anesthesia for localized pain

03/05 Special Considerations  Analgesia and sedation for painful procedures  For venipuncture: nonpharmacologic interventions plus topical and local anesthesia  For more invasive procedures, consider conscious sedation  Caution with midazolam: levels increased by some PIs and NNRTIs  Caution with fentanyl: respiratory and cardiac depression with loading doses in some patients on PIs or NNRTIs  Start at low dosages, titrate carefully, monitor closely

03/05 Special Considerations  Peripheral neuropathy  Appears to be less severe in children  Lidoderm patch, with other analgesics as needed  Discontinue precipitating medications, if possible  Neuropathic pain  Persists or intensifies independent of ongoing tissue injury or inflammation  May need combination therapy (nonnarcotics with or without narcotics)  Consult pain specialist

03/05 Special Considerations  Movement disorders  Consider levodopa  Consult with neurology, anesthesia, and rehabilitation specialists

03/05 Treatment of Specific Pain Syndromes IndicationGoals of TreatmentPharmacologic Approach Localized or regional pain due to tissue damage, inflammation, invasive infection, tumor Decrease inflammation and limit tissue damage; interrupt pain transmission; analgesia Topical analgesics; local anesthetics; capsaicin; topical steroids; NSAIDs; opioids; regional anesthesia Myopathic process Resolve underlying process; decrease inflammation Stop offending medications; maximize ARV therapy; NSAIDs; consider systemic steroids Systemic inflammatory process Decrease inflammation and stress NSAIDs; consider corticosteroids Peripheral neuropathy Limit inflammation and progression Lidoderm patch; tricyclic or SSRI; anticonvulsant; alpha2 agonist; stop offending medications

03/05 Treatment of Specific Pain Syndromes IndicationGoals of TreatmentPharmacologic Approach Neuropathic pain syndromes Modulation of CNS excitatory an sympathetic responses; decrease stress analgesia; mobilization Tricyclic or SSRI; alpha2 agonist; NSAID; anticonvulsant; opioid with NMDA blocking effect; NMDA receptor antagonist; systemic lidocaine; regional anesthesia Movement disorder with rigidity, spasticity Improve comfort and mobility GABA agonist; L-dopa; regional anesthesia Encephalopathic process with irritability, insomnia Improve sleep; decrease CNS inflammation GABA agonist; ARV; NMDA receptor antagonist; anticonvulsant

03/05 Treatment of Specific Pain Syndromes IndicationGoals of TreatmentPharmacologic Approach Respiratory distress or severe congestive heart failure Sedation and/or analgesia for comfort and to help tolerate interventions O2; morphine and other opioids; GABA agonist Escalating narcotic and anesthetic resistance Blunt excalation; preserve opioid responsiveness Alpha2 agonist; opioid with NMDA blocking effect; NMDA receptor antagonist Opioid or GABA agonist withdrawal Minimize stress responses; wean at tolerable rate Alpha2 agonist; opioid with NMDA blocking effect, long- acting GABA agonist

03/05 Conclusion  Pain may significantly diminish quality of life and complicate medical management  Optimal management often requires multidisciplinary collaboration (anesthesia, pain service, nursing, social services, others)