Julie Hauer, MD Medications and Dosages: A Supplement to Table 3.4 1

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1 Medications and Dosages: A Supplement to Table 3.4 in Caring for Children Who Have Severe Neurological Impairment: A Life with Grace, by Julie M. Hauer, M.D the Johns Hopkins University Press The following information is for physicians seeking suggestions with medication dosing that minimizes toxicity and maximizes an adequate trial. Use of any medication requires adequate knowledge of side effects and drug-drug interactions. These suggestions cannot replace medical judgment in how the individual characteristics of a patient influence decisions about the use of medications, including dosage. Many of these medications involve off-label use (not approved by the FDA for use in children). The goal of providing this information is to minimize the development of side effects when medications are increased too rapidly and when two medications with the same mechanism of action are used. At other times, an adequate trial may not occur as the result of a medication dose that is too low. Both problems can result in a failed trial resulting in a missed opportunity to know if the medication could have been beneficial for the problem. In general, the initial goal is to demonstrate that the medication is tolerated, at times accomplished by starting at a low dose and increasing the medication in increments that are tolerated. The next goal is to determine if the medication can provide adequate benefit for the problem, accomplished by determining a dose that provides benefit or a minimize dose within an accepted range of use before determining that the hoped for benefit has not occurred. Julie Hauer, MD Medications and Dosages: A Supplement to Table 3.4 1

2 Medications for empiric pain treatment Calculate initial dose using maximum weight of 50 kg Suggested Starting Dose (initial maximum starting dose) Mechanisms of action Neuropathic pain, central pain, and visceral hyperalgesia Gabapentinoids Gabapentin Day mg/kg (100 mg) PO TID OR 5 mg/kg (250 mg) PO qhs Day mg/kg TID OR 2.5 mg/kg am and afternoon and 5 mg/kg qhs Day 7 Increase every 2-4 days by 5-6 mg/kg/day until 1. Effective analgesia reached (often noted at mg/kg/day) 2. Side effects experienced 3. Maximum dose of mg/kg/day ( mg total daily dose) 4. Titrate more rapidly for severe pain or as tolerated 5. See sample handout Thought to inhibit excitation by binding to the alpha-2-delta subunit of voltage dependent Ca ion channels in the CNS Comments Available as a liquid 50 mg/1 ml Side effects include sedation, nystagmus, tremors, peripheral edema, restlessness Sedation can be minimized by increasing the dose slowly and typically lessens with time No interactions with other drugs See gabapentin handout with sample schedules and instructions for family and other caregivers Julie Hauer, MD Medications and Dosages: A Supplement to Table 3.4 2

3 Sample gabapentin schedule handout with instructions for parents Gabapentin (50 mg/1 ml) Patient name Weight 15 kg Symptoms predominantly in the evening with associated disrupted sleep half of the total daily dose given in the evening Symptoms at different times of the day total daily dose divided equally across all three doses Day am afternoon evening Day am afternoon evening (6-8 am) (1-3 pm) (8-10 pm) (6-8 am) (1-3 pm) (8-10 pm) ml (75 mg) ml 0.5 ml 0.5 ml ml 0.8 ml 1.5 ml ml 1 ml 1 ml ml 0.8 ml 3 ml ml 1.5 ml 1.5 ml ml 1.5 ml 3 ml ml 2 ml 2 ml ml 1.5 ml 4.5 ml ml 2.5 ml 2.5 ml ml 2.3 ml 4.5 ml ml 3 ml 3 ml ml 2.3 ml 6 ml ml 3.5 ml 3.5 ml ml 3 ml 6 ml ml 4 ml 4 ml Further increases (every 2-4 days) Further increases (every 2-4 days) 3 ml 3 ml 7.5 ml 4.5 ml 4.5 ml 4.5 ml 3.8 ml 3.8 ml 7.5 ml 5 ml 5 ml 5 ml 3.8 ml 3.8 ml 9 ml 5.5 ml 5.5 ml 5.5 ml 4.5 ml 4.5 ml 9 ml 6 ml 6 ml 6 ml Can I increase the dose sooner? You can make increases sooner if your child has no significant sedation after the first one or two increases, such as increasing the dose every other day What dose should I stop at? Stop at the dose that provides a significant improvement in comfort Should I keep increasing gabapentin if my child is not better after one week? If symptoms continue and your child is tolerating gabapentin, increase to ml (or ml) before determining that gabapentin is NOT beneficial* How will I know if it is helping? Improvement will be indicated by a decrease in the frequency, duration, and severity of the following features: arching, stiffening, grimacing, crying, and retching, along with improvement in sleep** Can I stop gabapentin? Do not stop gabapentin abruptly; if a decision is made to stop gabapentin, a schedule will be provided to taper off over 7-14 days What are the side effects? Side effects include sedation (too sleepy), tremors, nystagmus (jerking eye movements), and restlessness in some What should I do if I notice side effects in my child? Call to determine next steps My child was doing well but is becoming irritable again. Can I increase the dose? If symptoms later return or increase, resume an increase in dose as outlined above and call our office When should I call the clinic? Call if no improvement once the minimum dose is reached, if side effects are experienced, if symptoms have returned, or if there are other concerns Call the clinic at [insert phone number] with any questions or updates *Indicate an individualized dose using a total dose of mg/kg/day for children less than 5 years and mg/kg/day for greater than 5 years of age; this will help ensure an adequate gabapentin trial Julie Hauer, MD Medications and Dosages: A Supplement to Table 3.4 3

4 **Provide an individualized list of features for each child Suggested Starting Dose Mechanisms of (initial maximum starting dose) action Comments Pregabalin See gabapentin Liquid now available Day 1-3 Day 4-6 Day 7 1 mg/kg PO qhs (50 mg) 1 mg/kg PO q 12 hour Increase every 3-4 days by 1 mg/kg/day until 1. Effective analgesia reached 2. Side effects experienced 3. Maximum total dose of 6 mg/kg/day divided into 2 or 3 doses per day (daily dose up to 12 mg/kg/day has been used) 4. Titrate more rapidly for severe pain No evidence that pregabalin provides greater benefit than gabapentin in children with SNI May have benefit of less frequent dosing Tricyclic antidepressants (TCAs) Nortriptyline or Amitriptyline Day mg/kg PO qhs (10 mg) Day mg/kg PO qhs Day 9 Increase every 4-5 days by 0.2 mg/kg/day until D 1. Effective pain relief reached or total dose of 1 mg/kg QHS (50 mg/day) 2. Obtain plasma level and ECG before further dose increases Presynaptic reuptake inhibition in the CNS of serotonin and norepinephrine, both inhibitors of pain transmission Serotonin-norepinephrine reuptake inhibitors (SNRIs) Venlafaxine mg PO daily for 1 week, then BID, then increase by mg every 4-7 days, maximum 225 mg/day Duloxetine 20 mg PO, increase by 20 mg weekly up to 60 mg q day, maximum 60 mg BID Other adjuvants Dronabinol mg/kg PO q 12 h (2.5-5 mg) May increase if tolerated to maximum of 10 mg twice daily Reuptake inhibition of serotonin and norephinephrine Cannabinoid receptor agonist (C 1 and C 2 ) Caution when using with other medications that increase serotonin levels (see table 4.2) Serum level ( ng/ml) seldom needed, though it can document adequate absorption in the GI tract Caution with other medications that can prolong QT interval Limited information on use in children Used for neuropathic pain in adults Caution in using with other medications that increase serotonin levels (see table 4.2) Duloxatine cannot be crushed (delayed-release capsule) Used for central pain in adults with multiple sclerosis Studies in children include use for nausea and vomiting Side effects include delayed gastric emptying, anxiety, depression, irritability, restlessness, and dry mouth Julie Hauer, MD Medications and Dosages: A Supplement to Table 3.4 4

5 Suggested Starting Dose (initial maximum starting dose) Pain medications Tramadol 1-2 mg/kg ( mg) PO q 4-6 hours as needed or scheduled. If using greater than 8 mg/kg/day (max 400 mg), change to an opioid, such as morphine sulfate. DO NOT use with opioids Morphine sulfate and other opioids mg/kg (10-15 mg) PO/SL q 3-4 hours as needed Methadone Requires expertise in use Mechanisms of action Mu opoiod receptor agonist, serotonin releasing agent, norephinephrine reuptake inhibitor Opioid receptor agonist, including mu receptors Mu opioid receptor agonist and NMDA receptor antagonist Comments Multiple properties may benefit specific types of pain treatment Caution with other drugs that increase serotonin (table 4.2) Caution in patients with seizures Beneficial for pain, dyspnea, and autonomic storms Theoretical benefit for neuropathic pain Requires expertise in use Julie Hauer, MD Medications and Dosages: A Supplement to Table 3.4 5

6 Opioid dosing and conversion (for children older than 6 months of age) Drug Equianalgesic Dose Oral Dose (maximum starting) Oral IV Oral, G-tube, buccal (mg) (mg) Morphine mg/kg q 3-4 h (10-15 mg) Oxycodone N/A mg/kg q 4 h (5-10 mg) Hydromorphone mg/kg q 3-4 h (1-2 mg) IV Dose (maximum starting) IV mg/kg q 2-4 h (2.5-5 mg) NA mg/kg q 2-4 h ( mg) Fentanyl N/A 0.1 (100 mcg) NA mcg/kg q 30 min (25-50 mcg) Methadone Requires expertise in use Requires expertise in use 1. Calculate initial dose using maximum weight of 50 kg 2. Maximum dose in parentheses indicates initial adult dose 3. These doses represent starting doses 4. q = every, indicating dose interval 5. Fentanyl 25 mcg/hr transdermal patch approximately 50 mg/day oral morphine 6. Methadone requires expertise, including knowledge of drug-drug interactions. Biphasic elimination may result in drug toxicity 3-7 days after starting or increasing methadone 7. Opioid conversion: reduce calculated dose of new opioid by 25-50% (50%-no pain, 25%-mild pain) due to incomplete cross-tolerance (e.g. due to differences in the structure of different opioids and their affinity for the various mµ receptors) Julie Hauer, MD Medications and Dosages: A Supplement to Table 3.4 6

7 Medications for problems of the central nervous system Calculate initial dose using maximum weight of 50 kg Suggested Starting Dose (initial maximum starting dose) Dysautonomia (Autonomic Dysfunction) Clonidine Day mg/kg PO qhs (max 0.1 mg) Day mg/kg q 12 hours Day mg/kg q 8 hours In addition: mg/kg q 4 hour prn autonomic storm Doses may be increased to maximum of mg/kg/dose (0.4 mg) Titrate more rapidly if tolerated Gabapentin and Pregabalin See Neuropathic pain section Cyproheptadine 0.08 mg/kg PO q 8 hr (4 mg); If no benefit in 3-5 days, increase doses by mg/kg Morphine Sulfate mg/kg PO/SL q 3-4 hr prn autonomic storm (10 mg) Benzodiazepines prn autonomic storm Clonazepam mg/kg ( mg) Diazepam mg/kg PO ( mg) Lorazepam mg/kg (2 mg) PO/SL Midazolam mg/kg (5 mg) PO/SL Propranolol mg/kg PO q 8 hr (20 mg), increase every 3 days to maximum of 1.6 mg/kg q 8 hr (80 mg) Bromocriptine mg/kg PO q 12 hr (maximum 1.25 mg) Mechanisms of action Centrally acting alpha-2 adrenergic receptor agonist, reducing sympathetic outflow See above 5HT 2, H 1 & Ach receptor antagonist CNS opioid receptors Increases affinity of GABA for GABA A receptors Beta-blocker D 2 receptor agonist Comments Goal with scheduled medications (gabapentin, clonidine, cyproheptadine) is to decrease frequency, duration, and severity of symptoms Goal with intermittent drugs (prn) is to lessen the duration and severity of autonomic storm episodes that occur despite scheduled medications Scheduled gabapentin may have greater benefit when features include agitation, stiffening, and intermittent spasms Cyproheptadine may have benefit when features of autonomic dysfunction include hypothermia or retching Propranolol decreases heart rate and blood pressure Conversion of oral clonidine to transdermal patch outlined below Guideline for converting from oral clonidine to transdermal patch: Day 1: apply patch, give 100% of oral dose Day 2: 50% of oral dose Day 3: 25% of oral dose Day 4: discontinue oral dose Converting from transdermal clonidine patch to oral: Start oral clonidine 8 hours after removing patch (clonidine level is maintained for approximately 8 hours after removing patch and then gradually decreases over several days) Julie Hauer, MD Medications and Dosages: A Supplement to Table 3.4 7

8 Spasticity and Muscle spasms Diazepam mg/kg PO/IV q 6 hr prn ( mg) Clonidine See dysautonomia Average daily dose for spasticity in one study was 0.02 mg/kg/day, with a maximum dose of mg/kg (0.6 mg) q 8 hour Tizanidine mg/kg qhs (2-4 mg), increase gradually up to mg/kg q 8 hr (maximum of 8-12 mg q 8 hr in adults) Baclofen mg PO tid, increase every 3 days by 5-15 mg/day to maximum of 60 mg/day Gabapentin See neuropathic pain Dystonia and Chorea Trihexyphenidyl 1 mg PO q day; increase every 3-5 days up to 2-5 mg tid; some children will benefit from and tolerate up to a total daily dose of mg Tetrabenazine 12.5 mg PO q day, increase weekly up to 25 mg bid Myoclonus Clonazapam mg/kg PO q 8-12 h ( mg) See benzodiazepines See dysautonomia See clonidine Modulates GABA B receptors See neuropathic pain Anticholinergic (M1 muscarinic receptor antagonist) Dopamine depletor See diazepam Diazepam best used short term (< 4 weeks) or intermittently for muscle spasms Clonidine and tizanidine have possible benefit as pain adjuvant Gabapentin studied in patients with multiple sclerosis Clonidine and gabapentin may be beneficial for children with SNI given difficulty in assessing pain as the trigger for muscle spasms or pain from muscle spasms Anticholinergic side effects of trihexylphenidyl may be managed with pyridostigmine Tetrabenazine used to treat chorea associated with Huntington s disease Tolerance may develop Risk of increased saliva and bronchial secretions Seizures acute therapy for prolonged seizure >5 minutes or cluster of seizures Lorazepam mg/kg buccal/pr/iv Q 15 min x 2 (2-4 mg) Midazolam 0.2 mg/kg buccal/intranasal/iv (10 mg) Diazepam rectal gel 2-5 years 0.5 mg/kg Q 15 minutes x 3 doses 6-11 years 0.3 mg/kg Q 15 minutes x 3 doses > 12 years 0.2 mg/kg Q 15 minutes x 3 doses Round dose to 2.5, 5, 10, 15, or 20 mg/dose See above See above See above Evidence that midazolam as effective and safe as rectal diazepam Julie Hauer, MD Medications and Dosages: A Supplement to Table 3.4 8

9 Medications for gastrointestinal problems Calculate initial dose using maximum weight of 50 kg Retching and Vomiting (receptor antagonists unless indicated otherwise) Cyproheptadine 5HT 2, H 1 & Ach 0.08 mg/kg PO Q 8 hr (4 mg) No benefit in 5 days, increase dose by mg/kg Ondansetron 5-HT mg/kg PO/IV q 8 h prn (4-8 mg) Metoclopramide D 2 - prokinetic Prokinetic: mg/kg PO/IV q 6 h (10 mg) Promethazine H 1, Ach, weak D mg/kg PO/IV q 4-6 h prn ( mg) Haloperidol D mg/kg PO q 8 h prn (0.5-1 mg) Scopolamine Ach Adolescents: 1.5 mg transdermal patch q 72 h Dronabinol C 1 and C 2 agonist (cannabinoid receptors) mg/kg PO 2-3 doses per day (2.5-5 mg) May increase if tolerated to maximum of 10 mg bid (not studied in children with SNI) Visceral hyperalgesia: see Gabapentinoids and Tricyclic Antidepressants (TCAs) Constipation Polyethylene Glycol Osmotic hydrant Senna liquid Colonic stimulant 2-6 yrs gm/kg qd ( gm qd) >6-12 yrs ml Q day 1/2 tablet Q day ml Q day 1 tablet Q day Lactulose Osmotic agent ml PO bid or 5-10 ml PO q 2 h until stool Milk of Magnesia Bisacodyl suppository Pediatric Fleets enema Osmotic agent Colonic stimulant Osmotic laxative ml PO daily or bid, give scheduled or as needed 1 suppository PR every day as needed 1 PR every other day as needed Intestinal motility Erythromycin Motilin agonist 2-5 mg/kg PO 4 times daily (maximum 250 mg), such as 15 minutes prior to meals Pseudo-obstruction Neostigmine Produces cholinergic activity Test dose mg/kg/dose IV/SQ (0.5-1 mg) with monitoring in the ICU (bradycardia, hypotension, increased airway secretions and bronchial reactivity), titrated up to 0.08 mg/kg/dose if needed (see chapter 5 for comments on SQ and oral dosing as options) Julie Hauer, MD Medications and Dosages: A Supplement to Table 3.4 9

10 Medications for respiratory symptoms Calculate initial dose using maximum weight of 50 kg Dyspnea (also referred to as shortness of breath or uncomfortable breathing) Morphine mg/kg PO q 4 hr prn (maximum initial dose 5 mg) Lorazepam mg/kg PO/SL/SQ q 6 hr prn (1-2 mg) Midazolam mg/kg PO/SL (5 mg) Respiratory Secretions (acetylcholine receptor antagonists) Other opioids may be used at equivalent doses (equianalgesic dose) If on an opioid, increase dose by 30-50% Midazolam has a more rapid onset and shorter duration compared to lorazepam Glycopyrrolate mg/kg PO q 8-12 hr (1-2 mg) Atropine 0.5% ophthalmic drops 1-2 drops SL q 4-6 hr prn Scopolamine Adolescents: 1.5 mg by transdermal patch q 72 hr Hyoscyamine mg/ml solution 3-4 kg 4 drops PO/SL q 4 hours prn 10 kg 8 drops PO/SL q 4 hours prn 50 kg 1 ml (0.125 mg) PO/SL q 4 hours prn mg/5 ml elixir 10 kg 1.25 ml PO q 4 hours prn 20 kg 2.5 ml PO q 4 hours prn 40 kg 3.75 ml PO q 4 hours prn 50 kg 5 ml (0.125 mg) PO q 4 hours prn Care must be taken to minimize secretions that become thick and difficult to mobilize Medication use can be increased at end-of-life to assist with symptom management Side effects include constipation, urinary retention, and paradoxical agitation Review if on clonazepam, which can significantly increase bronchial secretions in some Julie Hauer, MD Medications and Dosages: A Supplement to Table

11 Management of escalating symptoms at the end of life General guidelines for management of escalating pain with an opioid (Moryl, et al. 2008) Titrate with IV dose every 15 min until pain is relieved (or PO dose every 60 min) If on opioids, initial bolus will be 10-20% of the 24 hour opioid dose Increase opioid bolus by 40-50% every third dose if pain continues Once patient has obtained adequate pain relief, calculate the new 24 hour opioid dose including rescue doses Determine route for around the clock dosing that is best suited to patient s ongoing analgesic needs (oral, IV, transdermal) Consider adding an adjuvant or coanalgesic (eg, a nonsteroidal anti-inflammatory drug, benzodiazepine, corticosteroid, or ketamine) If the patient has significant opioid adverse effects with adequate pain control, reduce the equianalgesic dose of the new opioid by 25-50% If the patient has significant opioid adverse effects without adequate pain control, rotate opioids without a reduction in the equianalgesic dose Seizures and agitation at the end of life (patients with DNR/DNI orders) Lorazepam mg/kg PO/buccal Q 6 or Q 8 hour (2 mg) Midazolam Intermittent Continuous mg/kg PO/SL (5-10 mg) Loading dose mg/kg (2 mg) then mg/kg/hr IV/SQ infusion titrated to effect Phenobarbital 1-5 years 3-4 mg/kg PO BID 5-12 years 2-3 mg/kg PO BID >12 years mg/kg ( mg) PO BID Multiple sources used for tables including: Increases affinity of GABA for GABA A receptors Increases affinity of GABA for GABA A receptors Enhances inhibitory action of GABA, inhibits excitatory action of glutamate Lexi Comp's Pediatric Dosage Handbook: 18th ed Schechter NL, Berde CB, Yaster M (Eds). Pain in Infants, Children, and Adolescents, 2 nd Ed. Philadelphia: Lippincott Williams and Wilkins, 2002 Goldman A, Hain R, Liben S (Eds). Oxford Textbook of Palliative Care for Children, 2 nd Ed. New York: Oxford University Press, 2012 Wolfe J, Hinds P, Sourkes B (Eds). Textbook of Interdisciplinary Pediatric Palliative Care, Philadelphia: Elsevier, 2011 Moryl N, Coyle N, Foley KM Managing an acute pain crisis in a patient with advanced cancer: "this is as much of a crisis as a code". JAMA 299(12): Abbreviations Ach = acetylcholine, D2 = dopamine, GABA = gamma-aminobutyric acid (inhibitory neurotransmitter involved with regulating neuronal excitability), H1 = histamine, IV = intravenous, PO = per os (by mouth), PR = per rectum, 5HT = serotonin, SL = sublingual/buccal, SQ = subcutaneous, q = time interval between each dose, agonists stimulate the receptor, antagonists block the receptor, qhs = give at nighttime Julie Hauer, MD Medications and Dosages: A Supplement to Table