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OBJECTIVES• Discuss the current evidence regardingopioid therapy for chronic non-cancer pain• Describe the role of non-opioid therapy forcommon painful conditions• Explain the relative risk vs. safety profiles ofopioids vs. non-opioid analgesics

DISCLOSURES• There are no real or perceivedfinancial, litigational, or other conflictsof interest to disclose


CHRONIC PAIN STATES• Chronic pain common– 10% prevalence– Major cause of missed work– >25% of patients with chronic pain receivedisability or injury compensation• Co-existing depression common

FIBROMYALGIA• Chronic condition characterized byphysical and psychiatric symptoms• Common complaints:– Widespread pain– Fatigue– Decreased mood/volition– Morning stiffness

FIBROMYALGIA• Etiology of pain not well understood• Proposed that pain is due to:– Central sensitization– Central disinhibition– Dysfunctional hypothalamic-pituitaryadrenal axis

FIBROMYALGIA• Commonly used therapies:– Opiates– NSAIDS– Steroids– Antidepressants– Anticonvulsants– Muscle relaxants• NSAIDS, steroids not clearly beneficial

NEUROPATHY• Chronic, painful condition• Due to injury or disease of CNS or PNS• Heterogeneous state of conditions– Diabetes– HIV– Trauma (CRPS)

NEUROPATHY: PROPOSEDMECHANISMS• Vascular– Advanced glycation of arterial walls– Ischemic proximal nerve lesion– Increased free radical injury– Nerve hypoxia– Epineural vessel atherosclerosis• Metabolic– Various enzyme deficiencies


• SSRI’s– Paroxetine– FluoxetineFIBROMYALGIA:ANTIDEPRESSANTS• NSRI’s– Duloxetine– Milnacipran

NEUROPATHY:ANTIDEPRESSANTS• Most data is for use of TCAs– Beneficial in most disease states exceptHIV– Cochrane: NNT 3.6 for at least moderatepain relief• Moderate data for SNRI’s, and likely asefficacious as TCAs• Limited data on SSRIsBriley M, Moret C. CNS Spectr. 2008; 13:22-6.Saarto T, Wiffen PJ. Cochrane Database Syst Rev. 2007; CD005454.

PREGABALIN• GABA analog that binds to the α 2 δ subuniton voltage-gated calcium channels• Beneficial in both fibromyalgia andneuropathic pain– Dose response– 150 mg daily generally ineffective– Most benefit from 600 mg daily

GABAPENTIN• Exact mechanism of action unknown• Does not bind to GABA receptor• Structurally related to GABA• Meta-analysis with at least moderateimprovement in 43% of subjects• Adverse events common (66%)Moore RA, Wiffen PJ, Derry S, et. Al. Cochrane Database Syst Rev. 2011; 16:CD007938

CARBAMAZEPINE• Inhibit multiple channels including:– Na channels hyperpolarization– Muscarinic/nicotinic ACh receptor– NMDA (glutamate) receptors– CNS adenosine receptor• Metabolized to active metabolite viaCYP3A4

CARBAMAZEPINE• Numerous studies– Most very small and of short duration• Meta-analysis reveals effective option forchronic neuropathic pain, but adverseeffects common– 66% for CBZ, 27% for placebo)


CHRONIC LOW BACK PAIN• Evidence for exercises much greaterthan for acute low back pain• Meta-analysis of 38 studies foundminimal role for opiates in CLBP– Mild efficacy, significant chance ofaddiction

CHRONIC LOW BACK PAIN• NSAIDS beneficial, withmaximal efficacy at 4weeks• No evidence to supportNSAIDS in CLBP• Cyclic antidepressants(esp. nortriptyline)beneficial


NEPHROLITHIASIS• Common condition:– Lifetime prevalence:• 12% for men• 6% for women– More than 2 millionvisits annually

NEPHROLITHIASIS:MECHANISM OF PAINObstruction in ureterHydronephrosisPressure against Gerotas fasciaLocal synthesis/release of prostaglandinDiuresis intrarenal pressureUreter spasm

NSAIDS VS. OPIATES INNEPHROLITHIASIS: THE VAS• Difference of 4.6 (1.7-7.5) mm favoring NSAIDSHoldgate A , Pollock T BMJ 2004;328:1401

NSAIDS VS. OPIATES:NEED FOR RESCUE ANALGESIA• Patients receiving NSAIDS less likely to needrescue analgesia (RR 0.75; 0.61-0.93)Holdgate A , Pollock T BMJ 2004;328:1401

NSAIDS VS. OPIATES:INCIDENCE OF VOMITING• RR = 0.35 (0.18-0.49)Holdgate A , Pollock T BMJ 2004;328:1401

OPIATES AND NSAIDS• Limited number of studies with 3 arms• Addition of opiates to NSAIDS hasbeen shown to result in:– Decreased pain– Possibly increase side effectsCordell WH, wright SW, Wolfson AB, et al. Ann Emerg Med. 1996; 28:151Safdar B, Degutis LC, Landry K, et. al. Ann Emerg Med. 2006; 48:173

α ANTAGONISTS• Inhibit ureteral musculature contractions• Reduce basal tone• Decreased peristaltic frequency andcolic pain• Demonstrated to reduce analgesicrequirements, colic episodes, and needfor hospital admission

Seitz C, Liatsikos E, Porpiglia F.Euro Urol. 2009; 56:455-71.

MIGRAINES• Affect 15% of population• 3.4 million annual ED visits for headache• Non-opiate options:– NSAIDS– Triptans– Phenothiazines– Dihydroergotamines– Propofol– Ketamine– Calcitonin gene related peptide (CGRP)

MIGRAINE: PATHOPHYSIOLOGY• Historically felt to be vascular• Aura due to vasoconstriction• Headache due to vasodilation• New theory involves activation oftrigeminovascular system

TRIGEMINOVASCULAR SYSTEM• Pseudounipolar sensory neuronsoriginate from trigeminal ganglion• Stimulation of trigeminal ganglionreleases vasoactive peptides- Substance P- Calcitonin Gene Related Peptide (CGRP)- Neurokinin A

CALCITONIN GENE RELATED PEPTIDE• CGRP is a neuropeptide expressed intrigeminal ganglia nerves• CGRP causes vasodilation of cerebraland dural vessels• Infusion of CGRP induces migraines

CALCITONIN GENE RELATED PEPTIDE• Most widely studied GCRP antagonists- Telcagepant- Olcegepant• Appear to be at least as effective astriptans and superior to placebo• Not yet FDA approved

CALCITONIN GENE RELATED PEPTIDE• Prophylactic therapy:- Telcagepant bid x 3 months resulted inhigher rates of transaminitis- 4/09 Merck announced they would notbe seeking a New Drug Application• Merck Research Laboratories withdrewMK-3207, another CGRP receptorantagonist

CURRENT TREATMENT PRACTICES• Use of opiates for migraines variessubstantially (16-71%) in US EDs• Treatments rendered– Dopamine antagonists (68%)– Opiates (64%)– NSAIDS (33%)– Migraine-specific medications (

NSAIDS, APAP• APAP less potent than ASA• Comparing APAP to ketorolac;• 57% of patients with no-mild pain at 2hafter 400 mg of ibuprofen• NNT for ibuprofen 3-7; 5-12 for APAP• ASA and NSAIDS have efficacy similarto oral sumatriptan

OPIATES• Meperidine less effective and associatedwith more side effects than most otheropiates• Superior to low dose NSAIDS; less effectivethan phenothiazines or ergotamines• Risk of dependence, chronic migraines

TRIPTANS• Provide agonism at 5HT1 1D and 5HT 1B• Results in vasoconstriction of basilarartery and vessels in dura matter• Primary contraindications include:– CV disease– Basilar/hemiplegic migraine– Use ergotamine (24 hours)

ERGOTAMINE• DHE activates– 5HT 1B, 1D (as do triptans)– 5HT 1A, 1F and 5HT 2A, 2C and D 1, 2– Inhibits prostaglandin releasefrom glia preventstrigeminal nucleus caudalisactivation• Same contraindications astriptans, but can causeserotonin syndrome

EFFICACY• Cochrane review: ergotamine +caffeine less effective thansumatriptanMcCrory DC, Gray RN. Cochrane Database Syst Rev. 2003; 3:CD002915

PHENOTHIAZINESKelly AM, Walcynski T, Gunn B. Headache. 2009; 49:1324

PHENOTHIAZINES: EFFICACY• Incidence of orthostasis quite low withprophylactic intravenous fluids• With prophylactic IVF, chlorpromazineis superior to ergot derivatives ormeperidine and similar to ketorolac,metoclopramide, and sumatriptan• Limited data on PO administration

KETAMINE AND MIGRAINE• Antagonist of the NMDA receptor• NMDA receptor mediated plasticity inchronic pain• Emerging data on analgesic benefits ofsub dissociative doses in several painfulconditions

• 17 migraine suffers• 80 mcg/kg SQ vs. saline for acute pain- Favors ketamine• Randomized, double-blind cross over forchronic pain with 80 mcg/kg SQ tid vs.saline strongly favors ketamine


PROPOFOL AND MIGRAINE• Numerous case reports and small caseseries with benefit• Largest study to date:- 77 patients with refractory migraine- 20-30 mg bolus q3-5 min- Mean dose 110 mg- 63 (82%) with complete resolution of HA- 14 (18%) with 50-90% improvement

SCIATICA: NSAIDS, OPIATES• NSAIDS superior to placebo• Equivalent to acetaminophen, butassociated with more side effects• All NSAIDS, including selective COX-2inhibitors equally effective• Opiates may be beneficial for acute pain;benefit in chronic pain questionableRoelofs PD, Deyo RA, Koes BW, et. al. Cochrane Database Syst Rev. 2008; 23:CD000396Martell BA, O’Connor PG, Kearns RD, et. al. Ann Intern Med. 2007; 146:116-27.Deshpande A, Furlan A, Mailis-Gagnon A, et. al. Cochrane Database Syst Rev. 2007; 18:CD004959

SCIATICA: STEROIDS• No benefit fromsteroidadministration

“MUSCLE RELAXANTS”• Some evidence supporting carisoprodol,cyclobenzaprine, orphenadrine, ortizanidine compared with placebo• Poor data supporting metaxalone,metocarbamol, baclofen vs. placebo• Insufficient data comparing efficacyChou R, Peterson K, Helfand M. J Pain Symptom Manage. 2004; 28:140


DEPENDENCE/ADDICTION• Most opiates have ability to causedependence and associated withabuse• Well known withdrawal syndrome• Tramadol exception• SSRIs, SNRIs, TCA associated withpotential withdrawal syndrome but lowabuse potential

TRAMADOL: ADVERSE EVENTS• Most adverse events involve GI or CNS• Anorexia, fatigue, constipation morelikely in those > 65 years,• AE most likely with CR or ER formulations• Seizures possible

GABAPENTIN• Two-thirds of patients taking 1200+ mggabapentin for neuropathy develop atleast one adverse event (vs. 51%placebo)– Adverse events result in 12% withdrawalrate from studies (RR 1.36; 1.09-1.71)– Dizziness, somnolence, peripheral edemaMoore AR, Wiffen PJ, Derry S, et. Al. Cochrane Database Syst Rev. 2011; CD007938

PREGABALIN• Pregabalin associated with dizziness,ataxia, visual changes, confusion• NNT: 5 NNH: 11Quilici S, Chancellor J, Lothgren M, et. Al. BMC Neurol 2009; 9:6

LONG TERM USE OF NSAIDS:• CV events:CV ADVERSE EVENTS– Greatest rate of MI:Rofecoxib (RR 2.12;1.26-3.56)– Greatest rate of CVA:Ibuprofen (RR 3.36;1-11.6)Trelle S, Reichenbach S, Wandel S, et. al. BMJ. 2011; 342:c7086

LONG TERM USE OF NSAIDS:GI ADVERSE EVENTS• Pooled risk of UGIB afterNSAIDS 3.8 (3.6-4.1)• Dose response• Minimal variation in riskbetween individual NSAIDSwhen compatible dosesconsideredHernandez-Diaz S, Rodriguez LA. Arch Intern Med. 2000; 160:2093-9

ANTIDEPRESSANTADVERSE EVENTS:• TCA’s associated with orthostasis andantimuscarinic symptoms• SSRI’s mostly associated with GI illness• Discontinuation syndrome

CARBAMAZAPINE: ADVERSEEVENTS• Somnolence/dizziness reported in > 50%of subjects taking CBZ• Rare, but serious adverse events:– SIADH– SJS– Bone marrow suppression– Anticonvulsant Hypersensitivity Syndrome(AHS)

CONCLUSIONS• Opiate use is common, but not alwaysthe most appropriate therapy• Various antidepressants (e.g. TCA’s,SNRI’s) and some anticonvulsants maybe effective in treating chronic painfulconditions

CONCLUSIONS• NSAIDS, alpha antagonists should beused for treatment of nephrolithiasis• Acute migraine headaches can betreated with phenothiazines, NSAIDS,triptans, and ergotamines– Ketamine and propofol in future?


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