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Chronic opioid therapy in headache. Richard Wenzel, Pharm.D. Diamond Headache Clinic Inpatient Unit Chicago, IL. Disclosures. Speaker’s bureau, GlaxoSmithKline. Grim data. The United States of America: constitutes ~ 5% of the world’s population

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Chronic opioid therapy in headache

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chronic opioid therapy in headache

Chronic opioid therapy in headache

Richard Wenzel, Pharm.D.

Diamond Headache Clinic Inpatient Unit

Chicago, IL

  • Speaker’s bureau, GlaxoSmithKline
grim data
Grim data

The United States of America:

  • constitutes ~ 5% of the world’s population
  • consumes 80% of the global legal opiod supply
  • consumes 99% of the global hydrocodone supply
  • consumes 66% of the global illegal drug supply

Pain Physician 2008:11:S63-S88

opioids in chronic pain systemic review of efficacy and safety
Opioids in chronic pain: systemic review of efficacy and safety
  • 11 trials
  • Mean pain relief ~ 30%
  • Only 44% of open-label opiod patients elected to continue therapy
  • Dropout rate due to side effects ~ 33%
  • 5 of 8 studies failed to show improved function

Kalso E, et al. Pain 2004;112:372-380

laboratory monitoring of oxycontin oxycodone clinical pitfalls
Laboratory monitoring of Oxycontin™ (oxycodone): clinical pitfalls
  • Suspected patient of abusing or misusing (selling?) OxyContin™
    • Frequent requests for dose escalation due to poor headache pain control
  • Urine-based immunoassay oxycodone drug screen was negative
  • Dismissed the patient from the physician’s practice
  • At the (distraught) patient's request, a second test using gas chromatography- mass spectrometry (quantitative, more sensitive) was performed on original urine sample, results were positive
  • For the urine-based immunoassay, the minimum level threshold was too high to detect the presence of oxycodone
  • Communication is essential

Von Seggern RL, et al. Headache 2004;44:44-47.

end organ damage possibly associated with chronic migraine
End Organ Damage Possibly Associated With Chronic Migraine

“…..exposure to repeated attacks and sustained doses of analgesics appears to result in brainstem changes as patients progress from EM to CM…..they [brainstem changes] will tend to increase attack frequency and hence analgesic consumption.”

Aurora SK, et al. Headache 2007;996-1003.

Accompanying editorial comment – Dodick DW. Headache 2007;1004-1007

Welch KMA, et al. Headache. 2001;41:629-637; Kurth T, et al. BMJ. 2011;342:c7357; McWilliams L, et al. Pain. 2004; 111:77-83; O’Bryant SE, et al. Headache. 2006;46:1364-1376; Bigal M, et al. Headache. 2006;46:1334-1343; Breslau N, et al. Neurology. 2003;60:1308-1312.

u s headache consortium evidenced based migraine treatment guidelines
U.S Headache Consortium evidenced-based migraine treatment guidelines

Neurology 2000;55:754-762

American Academy of Family Physicians

American Academy of Neurology

American Headache Society

American College of Emergency Physicians

American College of Physicians/American Society of Internal Medicine

American Osteopathic Association

National Headache Foundation.

general goals us consortium
General goalsUS Consortium

Establish diagnosis

Educate patient

Preventive/acute drugs, devices, limits of use

Set realistic expectations

No cures, only management

Create formal management plan

Avoid precipitating causes

stratified care
Stratified care

Endorsed by U.S. Headache Consortium

Stratified-care - assess aggregate burden of migraine on patients’ lives, patients suffering most debilitating illness are prescribed migraine specific drugs from the onset

stratified care1
Stratified Care



Low Need




Moderate Need

OTCs, Rx

High Need

Migraine Rx, Preventive Rx

migraine drug therapy
Migraine drug therapy


Intended to halt or significantly reduce an attack that is occurring or is about to occur


Decrease frequency, severity, or duration of attacks

acute treatment goals us consortium
Acute treatment goalsUS Consortium

Treat attacks rapidly and consistently without recurrence


Minimize use of rescue medications

Optimize self-care

Be cost-effective

Minimal adverse effects

Headache 2006;46:773-780.

quality of evidence a scientific effect clinical impression us consortium
Quality of evidence = AScientific effect = ++/+++Clinical impression = ++/+++US Consortium

Triptans by oral, nasal, subcutaneous

Dihydroergotamine intranasal

“limit use due to increased risk of rebound and dependency”

  • Butorphanol nasal spray
  • Acetaminophen plus codeine
quality of evidence b
Quality of evidence = B
  • “Limit use. Reserved for emergency department use or rescue medication.”
  • Butorphanol IM
  • Meperidine IM/IV
  • Methadone IM
narcotic use among headache sufferers
Narcotic use among headache sufferers
  • American Migraine Prevalence and Prevention Study (AMPP); longitudinal, population-based
  • Questionnaires sent to 120,000 U.S. households
  • ~78,000 responses
  • Narcotic data from subset analysis of ~ 28,000 “severe headache” patients, 2005 to 2009

Headache 2012;52:18-36.

medication use among all migraineurs
Medication use among all migraineurs
  • 18% triptans
  • 12% narcotics
  • 6% butalbital-containing product

Headache 2012;52:18-36.

ampp narcotic use among severe sufferers
AMPP narcotic use among “severe” sufferers
  • 70% non-narcotic users
  • 16% current narcotic users (within last 90 days)
  • 14% previous users (use during 2005-2008, but no current use)
  • Among narcotic users:
    • 66% used one narcotic agent
    • 20% use two agents
    • 8% used three agents
    • 94% also consumed at least one non-narcotic headache medication
ampp narcotic use among severe sufferers1
AMPP narcotic use among “severe” sufferers
  • 42% were prescribed hydrocodone product
  • 23% acetaminophen with codeine
  • 21% acetaminophen with propoxyphene
ampp narcotic use among severe sufferers2
AMPP narcotic use among “severe” sufferers
  • Compared to non-narcotic users, narcotic users had statistically significantly more:
    • Depression and/or anxiety
    • Consumption of health care resources (physician visits, ER visits, specialists visits)
    • Likelihood to be unmarried, unemployed, and have a lower household income
when to consider chronic narcotics for headache
When to consider chronic narcotics for headache?
  • Individualized
    • Greater than 15 days/month, intractable severe pain unresponsive to reasonable outpatient (inpatient?) therapies administered over the span of months to years
    • Absence of significant psychiatric disorders, including absence of addiction history
  • Practitioner dependent
    • Knowledge with prescribing nacotics - > consider referral
    • Resources for continual monitoring
  • Established practitioner/patient relationship
scheduled narcotic therapy for chronic headache
Scheduled narcotic therapy for chronic headache
  • Potential advantages
    • Improved functionality
    • Provides continuous, often pre-emptive pain-relief
    • Restore proper pathophysiology of dysfunctional CNS opioid functions?
    • Improved quality of life
    • others
  • Potential disadvantages
    • Tolerance/habituation
    • Misuse/abuse
    • Medication-induced headache/hyperalgesia?
    • tolerability
some keys to success
Some keys to success
  • Consider narcotic contract with patient
    • Single prescriber, no replacements for “lost” prescriptions, no “missed” appointments, family/partner input
  • Documentation
    • indication, expected benefits/risks, reasons for discontinuation, potential for withdrawal, etc.
  • Psychological services – initial and ongoing
  • Routine monitoring
    • functional status
    • adverse effects
    • inappropriate use – self-treating anxiety, insomnia, etc.
    • drug screen
more keys
More keys
  • Educate patient
    • Sparse published literature to support opioid use
    • Little long-term efficacy data
    • No long-term safety studies
    • Realistic expectations
daily scheduled opioids for intractable head pain
Daily scheduled opioids for intractable head pain

Saper J, et al. Neurology 2004;62:1687-1694





Saper, Neurology 2004

program description
Program description
  • Three year follow-up
  • Treatment contract
  • “Rescue” drugs as needed for exacerbation
  • Psychological interventions
  • Side effect management

Saper, Neurology 2004

patient enrollment
Patient enrollment

Total # 160 (100%)

Continued program at least 3 years 70 (44%)

Discontinued program 55 (34%)

Lost to follow up 18 (11%)

Transferred to local MD 10 (6%)

Died (all non-headache related) 7 (4%)

Saper, Neurology 2004

medications prescribed
Medications prescribed
  • Morphine
    • 52 patients (74%), median dose = 150mg (60mg-900mg)
  • Oxycodone
    • 14 patients (20%), median dose =85mg (10mg-360mg)
  • Methadone
    • 13 paients (19%), median dose = 30mg (7.5mg-70mg)
  • Fentanyl
    • 4 patients (6%), mean dose = 75mcg (8mcg-75mcg)

Saper, Neurology 2004

outcome measures
Outcome measures
  • Patients with at least 50% pain reduction at 3 years
    • 26% of initially enrolled patients (41/160)
    • 59% of 3-year patients (41/70)

Saper, Neurology 2004

other 3 year data
Other 3-year data
  • 67% reached 50% HI improvement within 1st month
  • No reduction in prophylactic or other rescue drugs
  • Efficacy unrelated to gender, diagnosis, anxiety/depression
  • Despite structured program (patient screening, contract, frequent visits, psych services, etc.) problem drug behavior observed in more than 50% of patients

Saper, Neurology 2004

warning signs
Warning signs

Dose escalation requests Self-initiated dose escalations

Early refill requests Emergency Dept visits

Missed appointments Lost prescriptions

Forgery of prescriptions Multiple prescribers

Conflicting history others

Communication is essential

paradoxical hypersensitivity
Paradoxical hypersensitivity
  • Triptan efficacy decreases if a narcotic has been consumed within the previous 6 months
  • Opiod-induced hyperalgesia?
  • May lower pain-sensation threshold
    • NMDA receptor-mediated neurotoxicity?
    • Down-regulation of opiod receptors?
    • Increase in excitatory neuropeptides?
  • Often marked by allodynia and worsening pain despite increasing narcotic doses
    • Possibly irreversible

Headache 2012;52:467-482

Anesthesiology 2006;104;570-587.

Headache Curr 2006;3:53-62.

J. Curr Pain Headache Rep 2006;10:67-70.

other unpublished data
Other unpublished data
  • Methadone only agent prescribed
    • 2.5mg-10mg tid
    • Antagonizing glutamate
  • 70% of “positive treatment response” patients at two months maintained this response at one year
  • “….represent a less complex group of patients..”

Rothrock JF. Headache 2008;48:850-854.

Rothrock JF. Headache 2007;47:1232-1233.

acute migraine medications and evolution from episodic to chronic migraine ampp
Acute migraine medications and evolution from episodic to chronic migraine: AMPP

“Compounds containing barbiturates and opiates were associated with a twofold increased risk of [transformed migraine]”

- barbiturates OR 2.06, 95% CI = 1.3-3.1

- opiates OR = 1.98, 95% CI 1.4-2.8

Mean days/month of exposure

Barbiturates = 10.74

Opiates = 9.91


Headache 2008;48:1157-1168.

evolution of chronic migraine
Evolution of Chronic Migraine

Chronic Migraine

Episodic Migraine



Mood and anxiety disorders



Sleep disorders and IBS



Medication overuse


Cady R, et al. Curr Pain Headache Rep. 2005;9:47-52.

dependence related behavior in medication overuse headache moh
Dependence-related behavior in medication-overuse headache (MOH)
  • 80% of individuals presenting to specialized headache centers with CDH are over-using acute medications, majority of which are narcotics
  • Lack of universally accepted MOH definition
  • MOH cause of, or consequence of, chronic headache
  • Difficult to determine without psychological assessment
  • Referral?

Headache 2010;50:1597-1611

medication overuse headache moh and dependence
Medication overuse headache (MOH) and dependence
  • Risk factors for dependence on acute medications
    • History of migraine, history of opiod overuse, previous withdrawal
  • “MOH thus appears to belong to the spectrum of addictive behaviors. In clinical practice, behavioral management of MOH should be undertaken besides pharmacological management.”

Headache 2008;48:1026-1036.

differences in the personality profile of moh suffers and drug addicts mmpi 2 results
Differences in the personality profile of MOH suffers and drug addicts: MMPI-2 results
  • MOH patient – chronic pain controls the user’s behavior (e.g. seeking medications to avoid pain)
  • Addict – drug use controls the user’s behavior (e.g. seeking medications for euphoria and/or avoid withdrawal)

Headache 2011;51:1212-1227.

patient failing therapy
Patient “failing” therapy

Failed several acute agents

Early intervention? Non-oral route?

Failed adequate trial of at least two preventives?

Consider referral

National Headache Foundation maintains a state-by-state list of headache physicians

Patients can obtain this list for free


migraine in emergency department
Migraine in Emergency Department
  • 219 patients
  • 68% had taken medication within 24 hours prior to ED
  • 5% were on preventive medications prior to admission
  • 63% had no documented discharge medication
  • 64% reported return of headache within 24 hours of discharge
  • Only 22% were pain free upon discharge from ED

Gupta MX, et al. Headache 2007;47:1125-1133.

treatment in ed
Treatment in ED

57 patients

65% given “migraine cocktail”

Only four patients given migraine specific drug

Per MD, 35% “headache resolved”, 29% “headache improved”

Not a single patient was able to return to normal function at discharge

Blumenthal H, et al. Headache 2003;43:1026-1031

Rankin L. Editorial. Headache 2003;43:1032-1033.

repeater phenomenon
“Repeater” phenomenon
  • 10% of ED headache patients are “repeaters”, accounting for 50% of all headache-related ED visits
  • In comparison to non-repeaters, repeaters are more:
    • Triptan-naïve
    • More alexithymic
    • Depressed

Headache 2010;50:348-356.

treatment in emergency department
Treatment in Emergency Department

Establish diagnosis

Hydration, antiemetic, & supportive measures

ED visits avoidable (or can be minimized) with improved education and outpatient therapy

Enroll in appropriate outpatient therapy


Diamond S, et al. Headache Quarterly 2001;12:183-194.

Diamond S, et al. Consultant 1999 (August):2313-2320.

Schwartz TH, et al. Headache 2002;42:519-522.

AAN. Neurology 1995;45:585-587.

treatment in ed1
Treatment in ED

Supported by RCT

DHE 0.25mg –1mg IV, IM, SC Sumatriptan SC

Droperidol IV Magnesium 0.5gm-1gm IV\

Haloperidol IM

Supported by non-RTC evidence

Valproic acid (next slide)

Ketorolac 30mg-60mg IV, IM

Levetiracetam 500mg-1000mg

Metoclopramide IV

Antihistamines (diphenhydramine IV/IM, hydroxyzine IM)

Selective use of narcotics (contracts?)

Headache 2012;52:114-128

Headache 2012;52:292-306

Headache 2012;52:467-482

rapid infusion valproic acid
Rapid infusion valproic acid

Recent and ongoing research

300mg – 1000mg per dose

May be given two to four times daily

May be given with oral formulations

Serum levels do not correlate with efficacy

Dilute in 50ml Normal Saline infused 5 to 15 minutes

Can be diluted 1:1 in syringe for slow IV push

TERATOGENIC (need pregnancy test)

Norton J. Headache 2000;40:755-757

Edwards K, et al. Headache 2001;41-976-980

do butalbital containing products bcp have a role in the management of migraine
“Do butalbital-containing products (BCP) have a role in the management of migraine?”
  • Butalbital-containing products (BCP) given to 17% to 36% of diagnosed migraineurs, often as treatment of choice
  • National Ambulatory Medical Care Survey
  • #1 = BCP with 2.3 million prescriptions
  • BCP are well-established causes of dependency, withdrawal symptoms, MIH, poorly controlling migraine
  • Women are 164% more likely than men to get a BCP

Wenzel R, Sarvis C. Pharmacotherapy 2002;22(8):1029-1035.

Headache 2012;52:672-674

Headache 2010;50:1194-1197.


“Should butalbital-containing products be banned? Yes”Young M, Chiang Siow, H. Current Pain and Headache Reports 2002;6:151-155


“Why Should American Headache and Migraine Patients Still Be Treated With Butalbital-Containing Medicine?”

Tfelt-Hansen PC,Diener HC. Headache 2012;52:672-674

Scant evidence to support BCP or narcotics as migraine treatments, especially as drugs of choice

“No randomized, placebo-controlled studies prove or refute efficacy for [BCP] in the treatment of acute migraine headaches …. Based on concerns of over-use, medication overuse headache, and withdrawal, the use of [BCP] should be limited and carefully monitored.”

US Headache Consortium’s evidence-based migraine treatment guidelines



In an otherwise healthy, non-pregnant person, narcotics are difficult to rationalize as the treatment of choice for any primary headache disorder

Narcotics are woefully over-prescribed as initial treatments and in the Emergency Department…often yields unintended consequences

Narcotics work best as “rescue” medications for when migraine-specific medications fail, thus your goal is now pain relief, instead of reversal of the attack and return to normal function