OPIOIDS IN TREATMENT OF OPIOIDS IN TREATMENT OF CHRONIC NON CANCER PAINCHRONIC NON CANCER PAIN

Elias Veizi MD, PhDPain Medicine &Spine Care VAMC

Assistant Professor, Departments of Anesthesiology, Pain Medicine

Case Western Reserve UniversityCleveland, OH

OBJECTIVESOBJECTIVES

Pharmacology of opioids Effects and side effects of opioids Review the state of opioid prescribing UDT in chronic pain patients

DISCLOSURES: NONE

Nomenclature

Opium: dried powdered mixture of 20 alkaloids from the seed capsules of the poppy

Opiate: any agent derived from opium (really only 3: codeine, morphine, thebaine)

Opioid: all substances with morphine like properties

Heroin

O

HOH

NH

CH3

HO1

23

4

5

6

7

8

9

10

11

12

1314

15 16 O

AcOH

NH

CH3

AcO1

23

4

5

6

7

8

9

10

11

12

1314

15 16

Morphine (Astramorph)Heroin (Diamorphine)(2X as potent as morphine)(Conversion of two -OH groups to -OAcfacilitates crossing of the BBB)

Easily enzymatically hydrolyzed to AcOH and HO-ArHO- Group is needed for activity

HO- Group not important to activity

I. Opioid Pharmacology

Body has its own analgesic systemThis in-built analgesia provides short-term relief from pain that enables an animal to escape from predators or extract themselves from a dangerous situation without being crippled with painOpioid analgesics utilise this system to provide controlled pain-reliefThis system is stimulated by other stimuli beside pain, including exercise and stress

PROOPIO-MELANOCORTIN

b-endorphin ()

PROENKEPHALINLeu-enkephalin () Met-enkephalin ()

PRODYNORPHINDynorphin A () Dynorphin B ()

a-neoendorphin () b-neoendorphin () Leu-enkephalin ()

(ENDOMORPHINS)????

I. Opioid Pharmacology: Endogenous system

I. Opioid Pharmacology: Receptors

CharacteristicsHighly specific, high affinity binding sitesReceptors subtypes

mu (μ) – euphoria, analgesia, physical dependence, respiratory depressionµ1 = supraspinal analgesia; µ2 = spinal analgesia

kappa (κ) – miosis, analgesia of pentazocine, sedation

delta (δ) similar to μ receptors, enkephalins natural agonists

N/OFQ – newest opioid receptor; orphanin natural agonists

I. Opioid pharmacology: mechanism of action

Secondary ascending neuron

Primary afferent nociceptor terminal

Ca2+ Ca2+

K+ K+

Neurotransmitter glutamate

opioid receptor

opioid receptor

Opioid

Opioid

Functional Effects Associated with the Main Types of Opioid Receptor

μ δ κ

Analgesia Supraspinal Spinal Peripheral

++++++++++

-++-

-+

++

Respiratory depression ++++++ ++ -

Pupil constriction ++ - +

Reduced GI motility ++ ++ +

Euphoria ++++++ - -

Dysphoria - - +++

Sedation ++ - ++

Physical dependence ++++++ - +

Morphine

Receptors

Cortico-Spinal

Peripheral Nerve

Spino-thalamic

5HTNAMorphine acts here

5%

25%

70%

Activation of the μ receptor by an agonist such as morphine

analgesia

sedation

reduced blood pressure

Itching

Nausea

euphoria

decreased respiration

miosis (constricted pupils)

decreased bowel motility often leading to constipation

Classification of AgentsAgonists

Opium derivativesmorphinecodeineheroin (semi-synthetic)hydromorphone (Dilaudid), oxymorphone (Opana)

semisynthetic derivatives of morphine

hydrocodone (Vicodin), oxycodone (Percodan; Oxycontin)semisynthetic derivatives of codeine

Classification of AgentsSynthetic opioidsmeperidine (Demerol)methadone (Dolophine) propoxyphene (Darvon) levorphanol (Levo-Dromoran)

Classification of AgentsOpioid antagonists

Drugs that bind to opioid receptors and may antagonize (pure antagonists) or partially stimulate (partial agonists).

Agonist – antagonists (partial agonists)pentazocine (Talwin) buprenorphine (Buprenex)butorphanol (Stadol) nalbuphine (Nubain)

Classification of AgentsPure antagonistsnaloxone (Narcan)naltrexone (ReVia)nalmefine (Revex)

Opioid Agonists

Morphine and its derivativesMorphine

L-isomers are active formExtract of Papaver somniferum; chief phenanthrene

alkaloid in opiumStandard analgesic for moderate to severe pain

Morphine PharmacologyCNS effects

AnalgesiaSelectively interfere with nociception of painAlso interferes with forebrain mechanisms for affective

reaction to pain

Action mediated via receptors in:dorsal horn of spinal cord (substantia gelatinosa)periaqueductal gray (PAG)dorsal raphe nucleiand limbic regions

Morphine PharmacologyCNS effects (cont.)

Behavioral effects: dysphoria as initial experience followed by euphoria – major contributor to abuse liability as well as relief of pain and anxiety

Sedation, drowsiness, and mental cloudingEmetic:

direct stimulation High doses depress vomiting center

Antitussive: direct action on medulla cough center to suppress cough reflex

Morphine PharmacologyCNS effect (cont.)

Respiratory depression: ↓ sensitivity of respiratory center to CO2 drive. ↓ both rate and depth of respiration. Overdose-death by respiratory failure.

Hypothalamus – slightly ↓ body temperature - ↓ ACTH, FSH, LH, TSH

Myosis (pin point pupils)↑ tone to spinal motoneurons at high dose

(muscle rigidity)Excitatory effect at high doses, e.g., convulsion

Morphine PharmacologyPeripheral actions

GI tract - ↑ tone, ↓ peristalsis – constipation (need to prevent and/or treat

constipation in patients taking opioids chronically) Biliary tract – gall bladder or bile duct spasm

due to ↑ biliary pressureUrinary tract - ↑ muscle tone → ↓ urinary

output

Morphine PharmacologyPeripheral actions

Cardiovascular system – Most opioids have little direct effect on the heart but may produce bradycardia

peripheral vasodilation and orthostatic hypotension as a result of CNS actions, and histamine release.

Cerebral vasodilation, ↑ intracranial pressure Indirect effect due to histamine release

Itching, sweating, redness of eyes Bronchoconstriction, ↓ bronchial secretions

Immunologic – suppression of function of NK cells. However, blocking pain with opioids may reverse pain-induced supression of immune function.

Morphine and its Derivatives

Pharmacokinetics Absorption

im or sc: rapid absorption; peak plasma level within 30 min po: rapid absorption; significant first pass effect, relatively low

oral/parenteral ratioAlternative routes of administration – an attempt to maximize benefit

and minimize side effects Patient controlled analgesia (PCA) Epidural Transdermal Transmucosal Intra-articular

Morphine PharmacologyPharmacokinetics

MetabolismRapid glucuronide conjugation in liver and intestine

80 - 90% may be metabolized during the first pass through the liver after an oral dose

Morphine-6-glucuronide (an active metabolite) 4 – 6X more potent than morphine may contributes significantly to analgesia when morphine given

chronically by oral route or with renal failureMorphine-3-glucuronide lacks analgesic effect but can cause

dysphoric side effects or seizures

Morphine PharmacologyPharmacokinetics

Distribution – widely distributedCrosses placenta limited amounts slowly enters the brain (ABC transporters and

hydrophilicity limit entry) EliminationPrimarily biotransformation~ 90% via kidney (as glucuronide)~10% in feces via bile

Morphine PharmacologyAcute toxic symptoms

Triadcoma, pinpoint pupils, respiratory depression

Treatment:Maintain respirationOpioid antagonist, preferably iv naloxone (may precipitate

withdrawal symptoms), repeat as needed (naloxone has a duration)

Morphine PharmacologyDrug interactionsCNS depressant effects may be prolonged or

exaggerated by CNS depressants: phenothiazines, MAOI, tricyclic antidepressants

Amphetamine in small dose may enhance morphine effect (mechanism not clear)

Morphine PharmacologyContraindications/cautionsBronchial asthmaEmphysemaLiver damageHead injuriesAcute alcohol usePrevious dependenceConvulsive disordersAbdominal pain of unknown origin

Synthetic OpioidsMethadone (Dolophine)

Primarily a μ agonist with actions similar to morphine exceptAlso glutamate antagonist at NMDA receptorsGreater oral effectivenessExtended duration of action in suppressing

withdrawalSlow onset. Long duration (T1/2 22 hr) may

accumulate8

8

Other Synthetic OpioidsMethadone (Cont.)

Tolerance develops more slowlyWithdrawal syndrome is long and relatively mildbasis of “methadone detoxification”; wean addicts

off of other narcotics with oral methadone for a few weeks.

May cause torsades de pointes. Use with caution in patient at risk for arrhythmias.

Low cost so payers are encouraging its use

Methadone therapy [prevention model considerations]

Appropriate selection of candidates based on medical and behavioral stability.

Methadone should not be used, or used very cautiously, in individuals with QTc prolongation higher than 500 ms or cardiopulmonary abnormalities.

Additional risk factors for TdP are: History of unexplained syncope or seizures Other medication usage that affect QTc or CYP 3A4

Pain patients likely to “doctor shop,” misuse methadone, or mix it with CNS depressants are not good candidates for methadone.

Because a subgroup of pain patients experience substance use disorders, it is critically important to assess for a history of substance use before initiating methadone treatment for pain.

Although risk factors should be carefully considered, circumstances exist (e.g. end of life) in which benefits of improving refractory pain may outweigh risks associated with methadone

J Gen Intern Med 25(4):305–9 2010

Methadone dosing considerations Elderly, medically compromised, and opioid-naïve individuals starting

on methadone require special dosing considerations.

Guidelines: Initial methadone doses for opioid-naïve patients should not exceed

15–30 mg a day for the first three days, and it may be as low as 1–2 mg in medically vulnerable patients.

In the US, the current package insert recommends starting methadone at 2.5–10 mg every 8–12 hours, with gradual titration, depending on efficacy and tolerability

Despite some variation in initial dosing, both guidelines advocate for a “start low and go slow” approach, vigilance in assessing signs of toxicity, and slow titrations upward when necessary.

If pain persists, rescue doses may be required to improve analgesia during initial stages of treatment.

Patients are encouraged to monitor pain states, doses taken, quality of sleep, mood, and activity level.

J Gen Intern Med 25(4):305–9 2010

Potential Risk Factors in Methadone Deaths

Potential risk factors for respiratory

depression

Advancing age

Medically compromised

Liver or cardiac pathology

Sleep apnea

Polysubstance use

Opioid-naïve/low tolerance

High doses of methadone

Rapid titration of methadone dosing

Potential risk factors for TdP:

Female gender

Electrolyte imbalance

Liver or pulmonary pathology

Unexplained syncope or seizures

Other drug and medication use, especially those that impact QTc or inhibit CYP 3A428

High doses of methadone

Prolonged QTc

Opioid Withdrawal

Other Synthetic OpioidsTramadol (Ultram) not strictly an opioid analgesicproduces part of its effects by binding to μ receptors. Also inhibits NE and 5HT reuptake. Risk of seizures

Understand the difference between

Tolerance= less pain relief with the same dose (not a contraindication for therapy)

Physical dependence= withdrawal symptoms may occur when mediation is stopped (it is not addiction)

Addiction=compulsive behavior seeking the drugs Pseudo addiction=Iatrogenic drug seeking behavior

(inadequate treatment of pain?!)

The consequences of drugs of abuse on the cellular elements of the CNS

A. Büttner (2011) Neuropathology and Applied Neurobiology37, 118–134 The neuropathology of drug abuse

Cerebral vascular changes in polydrug abusers

Photomicrographs illustrating the spectrum of cerebral vascular changes in polydrug abusers. (A) Small artery in occipital white matter showing concentric wall thickening. The surrounding perivascular space contains occasional macrophages and pigment deposition. H&E, original magnification ×200. (B) Small vessel in the orbital white matter with perivascular lymphocytic aggregates. H&E, original magnification ×200. (C) Endothelial proliferation in the dentate nucleus, H&E, original magnification ×200. (D) Endothelial hyperplasia in the parietal white matter, H&E, original magnification ×200.

A. Büttner (2011) Neuropathology and Applied Neurobiology37, 118–134 The neuropathology of drug abuse

White matter of polydrug abusers a widespread axonal damage

Immunohistochemistry demonstrating β-APP-immunopositive bundles and β-APP-immunopositive globular deposits in the pons of polydrug abusers, counterstained with haematoxylin, original magnification ×100.

A. Büttner (2011) Neuropathology and Applied Neurobiology37, 118–134 The neuropathology of drug abuse

Dependence

(1) Physical dependence follows invariably tolerance to repeated administration of an opioid ( type).

(2) Failure to continue administering the drug results in withdrawal or abstinence syndrome.

(3) The signs and symptoms of withdrawal are: Rhinorrhea, lacrimation, chills, gooseflesh (piloerection), hyperventilation, hyperthermia, mydriasis muscular aches, vomiting, diarrhea, anxiety, and hostility.

OPIOID PRESCRIBING: Tremendous increase in

prescribing

From 1997 to 2007, the milligram-per-person use of prescription opioids in the U.S. increased from 74 milligrams to 369 milligrams ↑ 402%

In 2000, retail pharmacies dispensed 174 million prescriptions for opioids; by 2009, 257 million prescriptions were dispensed ↑ 48%

http://www.whitehouse.gov/ondcp/prescription-drug-abuse

Prescription opioid analgesic deaths nationwide, from 2001-2005.

Lanier W L , Kharasch E D Mayo Clin Proc. 2009;84:572-575

© 2009 Mayo Foundation for Medical Education and Research

Increased prescription of opioids in million grams of medication

between 1997 and 2006

Crofford, L. J. (2010) Adverse effects of chronic opioid therapy for chronic musculoskeletal painNat. Rev. Rheumatol. doi:10.1038/nrrheum.2010.24

Data taken from www.justice.gov/dea/index.htm

Opioid use - statistics15% of chronic pain patients not treated with opioids had illicit drug use vs. 34% illicit drug use in patients treated with opioids.1

Patients with substance abuse are more likely to request & be prescribed opioids?

Patients prescribed opioids are more likely to develop co-morbid substance abuse issues?

1. Christo PJ, Manchikanti L, Ruan X, et al. Urine drug testing in chronic pain. Pain Phys

2011;14:123-43

Who is prescribing these meds?

90% of patients are on opioids prior to presenting to a pain center.1

Main prescribers of opioid analgesics are PCPs, followed by dentists and orthopedic surgeons. The main prescribers for patients age 10-19 are dentists.2

1. Manchikanti L, Damron KS, McManus CD, et al. Patterns of illicit drug use and opioid abuse in patients with chronic pain at initial evaluation: a prospective, observational study. Pain Phys 2004;7:431-7. 2. Volkow ND, McLellan TA. Curtailing diversion and abuse of opioid analgesics without jeopardizing pain treatment. JAMA 2011;305(13):1346-7

EVIDENCE?? A systematic review of randomized trials for

multiple opioids utilized for managing various chronic pain conditions, showed fair evidence for tramadol in managing osteoarthritis. For all other conditions and all other drugs excluding tramadol, the evidence was poor based on either weak positive evidence or indeterminate or negative evidence.

Manchikanti L, Ailinani H, Koyyalagunta D, et al. A systematic review of randomized trials of long-term opioid management for chronic non-cancer pain. Pain Phys 2011;14:91-121.

PCP prescribing habits

PCPs assessed regarding following of nationally accepted pain treatment guidelines before and after

2-hour interventionWhat % of PCPs discussed….

Comorbid depression 35% → 44% Functional status 38% → 49% Substance use 25% → 34% Side effects 14% → 20%

Corson K, Doak MN, Denneson L, et al. Primary care clinician adherence to guidelines for the management of chronic musculoskeletal pain: results from the study of the effectiveness of a collaborative approach to pain. Pain Med 2011;12:1490-1501.

Aberrant behaviors (cont.) Going to ER for opioid medication refills Requesting early refills Reporting lost or stolen prescriptions Not following up with appointments that do not involve dispensing opioids Motor vehicle accidents or arrests Abuse of illicit substances Reporting relief only from opioid medications

Consider opioid agreement for chronic pain patients who:

Who are at risk for abuse or misuse Who take opiates around-the-clock Who get care from several providers

Monitoring based on Risk Level

Low Moderate High

Aberrant behavior?

5% 28% 90%

Frequency of visits

Monthly Biweekly Weekly

UDS at initiation?

Yes Yes Yes

Other UDS Randomly Every visit Every visit

Pill Counts? No Consider Yes

Referral to psychiatry/addiction?

No Consider Yes

8

When to do Urine Drug Testing (UDT)

Consider testing for chronic pain patients: Who are on opiates and new to you Who have hx of prior substance abuse Who exhibit aberrant behaviors When starting new treatments To support a referral or a contract

WHY WHY URINEURINE??

Urine allows longer detection times than serum (blood)1

Good specificity, sensitivity, low cost, ease of use2

Currently we have the most data on use of urine

1. Moeller K, Lee KC< Kissack JC. Urine drug screening: practical guide for clinicians. Mayo Clin Proc 2008;83:66-76. 2. Manchikanti L, Malla Y, Wargo B, et al. Protocol for accuracy of point of care (POC) or in-office urine drug testing (immunoassay) in chronic pain patients: a prospective analysis of immunoassay and liquid chromatography tandem mass spectroscopy (LC/MS/MS). Pain Physician 2010;13:E1-22.

Drug Urine Detection Time

Heroin (6-MAM) 6-8 hours

Hydrocodone 1-2 days

Oxycodone 1-3 days

Morphine 3-4 days

Methadone 2-4 days

Benzodiazepines Up to 30 days

Cocaine 1-3 days

Amphetamine 2-4 days

PCP 2-8 days

Marijuana 2-7 days for casual use30 days for chronic use

IMPLEMENTATIONIMPLEMENTATIONScreening for opioid use/misuse helps build trust and strengthens the patient-physician

relationship

Discuss at the first visit in a non-confrontational way that this is like any other laboratory test

Cross-ReactivityCross-ReactivityDrug Cross-Reactants

Cannabis NSAIDs, protonix, marinol

Opioids Poppy seeds, chlorpromazine, rifampin, dextromethorphan

Methadone Propoxyphene, quetiapine

PCP Chlorpromazine, thioridazine, meperidine, diphenhydramine

Benzodiazepines

Oxaprozin (daypro)

Alcohol Asthma inhalers

FALSE-POSITIVES FOR FALSE-POSITIVES FOR ILLICIT DRUGSILLICIT DRUGS

A 2011 study on ~1,000 patients found1:0% for cocaine2% for marijuana~1% for amphetamines

Plan may include no prescription until confirmation or a limited supply (3-5 days)

1. Manchikanti L, Malla Y, Wargo BW, Fellows B. Comparative evaluation of the accuracy of immunoassay with liuqid chromatography tandem mass spectrometry (LC/MS/MS) of urine drug testing (UDT) opioids and illict drugs in chronic pain patients. Pain Physician 2011;14;175-88.

CONFIRMATORY TESTINGCONFIRMATORY TESTING

2009 retrospective study in 1 million patients utilizing UDT found1:

75% were likely not taking medication as prescribed38% had no detectable level of prescribed med29% had a non-prescribed med11% had illicit drugs.

While recommendations exist regarding use of UDT, none exist regarding use of POC vs confirmatory testing.

1. Couto JE, Romney MC, Leider HL, et al. High rates of inappropriate drug use in the chronic pain population. Popul Health Mang 2009;12:185-90.

INTERPRETING RESULTS – INTERPRETING RESULTS – 5 POSSIBILITIES5 POSSIBILITIES

1. + for prescribed drugs and – for all other drugs

Normal result2. - for prescribed drugs3. + for non-prescribed drugs4. + for illicit drugs5. Urine specimen tampered with

Christo PJ, Manchikanti L, Ruan X, et al. Urine drug testing in chronic pain. Pain Physician 2011;14:123-43.

URINE SPECIMEN URINE SPECIMEN TAMPERED WITHTAMPERED WITH

Cold urine, wrong pH, abnormal creatinine, etc.

Almost any possible explanation is incriminating

Consider as grounds for discharge.

- FOR PRESCRIBED - FOR PRESCRIBED DRUGSDRUGS

Send specimen for confirmation More restrictive compliance

monitoringo More frequent visitso Pill countso Change in formulation

+ FOR NON-PRESCRIBED + FOR NON-PRESCRIBED DRUGDRUG

False-positiveReview cross-reactantsSend for confirmationMetabolitesOpioids from another source

Review state prescription reporting data [OARRS]

MetabolitesDrug Metabolites

Hydrocodone Hydromorphone, dihydrocodeine

Oxycodone Oxymorphone, noroxycodone

Morphine M-3-G, M-6-G, normorphine, hydromorphone

Methadone EDDP

Hydromorphone

H-3-G, dihydromorphone

Oxymorphone O-3-G, oxymorphol

Codeine Hydrocodone, norcodeine, morphine

Heroin Morphine, codeine, 6-MAM

Fentanyl Norfentanyl

+ FOR ILLICIT DRUGS+ FOR ILLICIT DRUGS

~46% of patient with CNCP have history of illicit drug use and 8-23% are current users,

12% are actively abusing opioids.1,2

Continued illicit drug use is incompatible with opioid therapy

Discharge vs addiction medicine referral vs treatment.

1. Manchikanti L, Cash KA, Malla Y, et al. A prospective evaluation of psychotherapeutic and illicit drug use in patients presenting with chronic pain at the time of initial evaluation. Pain Phys 2013;16:E1-13. 2. Manchikanti L, Damron KS, McManus CD, et al. Patterns of illicit drug use and opioid abuse in patients with chronic pain at initial evaluation: a prospective, observational study. Pain Phys 2004;7:431-7

Opioid TherapyGuidelines for opioid treatment

Exhaust other conservative treatment options firstRule out contraindications to opioid useSingle practitioner prescribes all the opioidsProvide informed consent regarding side effectsOpioid contractAssess degree of pain relief, functional improvementPt should return at least monthly during dose titrationConsider tapering and discontinuation if contract

breachedConsider always alternative treatment

Thank you