Opioid-induced Hyperalgesia & Opioid Use Disorders: the Science and the Myths

Peggy Compton, RN, PhD, FAANVan Ameringen Endowed Chair

Dept of Family & Community HealthSchool of Nursing

Add mao

Content Outline

• Opioid-induced hyperalgesia (OIH)

• Overview and theorized mechanisms

• OIH in patients with opioid use disorder

• Implications for the perioperative setting

• How do we know if it’s there?

• Relationship to with tolerance and withdrawal

• Clinical diagnosis

• What do we need to know to move field forward?

Opioid-induced Hyperalgesia -

Increased sensitivity to pain resulting from opioid administration

Pain-free animal models have significantly decreased nociceptive

threshold following single or repeated administration of opioids

OIH is characterized by:

• Increase in pain intensity over time

• Spreading of pain to locations beyond the initial pain site

• Increase in pain sensation of external stimuli

Pain

tolerance

Opioid-induced analgesia

DESENSITIZATION

Opioid-induced hyperalgesia

SENSITIZATION

OIH as an Opponent Process

Opioid

administration

Adapted from: Solomon R, 1980; Koob GF et al., 1989

Preclinical OIH• Reduction in baseline pain thresholds

• Noted across nociceptive stimuli (thermal, chemical, electrical)

• Demonstrated across opioid (heroin, fentanyl, morphine)

• Demonstrated across route of administration (IV, SC, IT, IP, oral)

• Dose-dependent (cumulative dose/cumulative exposure)

• Increases incisional (wound) hyperalgesia

• Resolution of OIH is similar to time course of its development

• Large OIH response related to longer lasting OIH

• Intensified with antagonist precipitated withdrawal; worsens with repeated withdrawal episodes

• More robust in female animals

• Shares mechanisms underlying the development of neuropathic pain

Opioid-induced hyperalgesia in preclinical models

Li X, et al., Brain Res Mol Brain Res 2001;86:56-62.

Genetic propensity to develop OIH

Liang DY, et al., Pharmacogenet Genomics. 2006;16(11):825-35.

Theorized mechanisms of OIH neuroplastic changes to the peripheral and central nervous system that lead to sensitization of pro-nociceptive pathways

Adapted from Angst and Clark, 2006

Theorized mechanisms of OIH neuroplastic changes to the peripheral and central nervous system that lead to sensitization of pro-nociceptive pathways

Adapted from Angst and Clark, 2006

Peripheral neuron

Central neuron

GluGlu

Glu

Glu

NMDA-R

PKC

+

mu opioid-R

+ morphine Administration of opioid upregulates excitatory amino acid receptors in dorsal horn

↑ release of

pro-inflammatory cytokines

+

Peripheral neuron

Central neuron

Maier D, et al. , 2004 ; DeLeo JA, et al., 2004

GluGlu

Glu

Glu

NMDA-R

PKC

+

mu opioid-R

+ morphine

Glial cell

Interaction of inflammation and opioids on hyperalgesia

Martyn et al., 2019

Cold-pressor pain tolerance in current and formeropioid and cocaine abusers

0

30

60

90

120

150

180

opioid abusers cocaine abusers ex-opioid abusers ex-cocaine abusers

*

Compton, 1994*Pain tolerance negatively correlated to methadone dose; not associated with time on methadone

Co

ld p

ress

or

pai

n t

ole

ran

ce (

sec)

R03 HS06964 DHHS, AHCPR, PI: Compton

Cold-pressor hyperalgesia in pts with opioid use disorder on medication-assisted therapy (MAT)

Cold-pressor pain tolerance of methadone-maintained and matched control subjects, p<0.02

Cold-pressor withdrawal latency in persons with opioid use disorder on MAT and matched controls, p<0.05 Compton, et al., 2001

Compton, et al., 2000

Doverty et al., Pain, 2001

Comparison of mean (±SEM) pain detection and pain tolerance values at 0 and

3 h in MM patients and matched controls.

OIH in heroin abusers:

No change with

substitution therapy

OIH present at both

peak and trough

methadone blood levels

Compton et al., J Pain. 20124-8wks 12-18wks

OIH in Methadone pts with Chronic Pain

Hay et al., 2009 Journal of Pain, 10(3):316-22

Hyperalgesia present to same degree in MM patients with and without chronic pain

“At such times I have certainly felt it a great responsibility to say that pain, which I know is an evil, is less injurious than morphia, which may be an evil. Here experience is needed. Does morphia tend to encourage the very pain it pretends to relieve?”

“On the abuse of hypodermic injections of morphia,”Clifford Albutt, Practitioner 1870; 3:327-330

.

“ He is also affected by a hypersensitiveness to pain, or a morbid intolerance of any kind of distress …. He suffers. His suffering is actually great. To his astigmatic inner eye it seems even greater than it is.”

“What is the morphine disease?”Charles W. Carter Journal of Inebriety 1908;30:28-33.

OIH in opioid abusers - Not a new observation?

Hyperalgesia persists 28 days following opioid detoxification

Pain responses of opioid addicts (OA) and controls across the study

(means± S.D.). Y-axis latency, tolerance, and pain intensity. ***p ≤ 0.0001

between controls and OAs. No differences between the three time points in the

OAs group. Pud et al., Drug Alcohol Depend. 2006 May 20;82(3):218-23.

Genetic propensity to develop OIH

Liang DY, et al., Pharmacogenet Genomics. 2006;16(11):825-35.

C57BL/6J common inbred- Poor baseline pain tolerance

- Poor analgesia response- High opioid reinforcement

Is the hyperalgesia in patients on MATopioid-induced?

Cold

pre

ssor

pain

tole

rance (

sec)

Pain tolerantPain intolerant

Or are opioid abusers hyperalgesic by nature?

300

200

100

Walsh et al, 1989

Opioid abstinence and hyperalgesia*

* all data cross-sectional

On Opioids Ex-opioid Addicts Matched Controls

Martin & Inglis, 1965 X < X

Hole and Dole, 1979 X < X = X

Carcoba et al., 2011 X < X

Compton, 1994 X < X

Compton et al, 2001 X < X

Liebmann et al., 1997 X > X

Liebmann et al., 1998 X > X

Prosser et al., 2008 X > X

Pud, 2006 X < X

Ren et al., 2009 X < X

Triester et al., 2012 X < X = X

On MAT vs. drug-free

On Opioids Ex-opioid Addicts Matched Controls

Martin & Inglis, 1965 X < X

Hole and Dole, 1979 X < X = X

Carcoba et al., 2011 X < X

Compton, 1994 X < X

Compton et al, 2001 X < X

Liebmann et al., 1997 X > X

Liebmann et al., 1998 X > X

Prosser et al., 2008 X > X

Pud, 2006 X < X

Ren et al., 2009 X < X

Triester et al., 2012 X < X = X

On MAT vs. matched controls

On Opioids Ex-opioid Addicts Matched Controls

Martin & Inglis, 1965 X < X

Hole and Dole, 1979 X < X = X

Carcoba et al., 2011 X < X

Compton, 1994 X < X

Compton et al, 2001 X < X

Liebmann et al., 1997 X > X

Liebmann et al., 1998 X > X

Prosser et al., 2008 X > X

Pud, 2006 X < X

Ren et al., 2009 X < X

Triester et al., 2012 X < X = X

Drug-free recovery vs. matched controls

On Opioids Ex-opioid Addicts Matched Controls

Martin & Inglis, 1965 X < X

Hole and Dole, 1979 X < X = X

Carcoba et al., 2011 X < X

Compton, 1994 X < X

Compton et al, 2001 X < X

Liebmann et al., 1997 X > X

Liebmann et al., 1998 X > X

Prosser et al., 2008 X > X

Pud, 2006 X < X

Ren et al., 2009 X < X

Triester et al., 2012 X < X = X

Pain ratings (0–100)

for punctuate

mechanical stimuli

Edwards RR ,et al. The Journal of Pain, Volume 12, Issue 9, 2011, 953–963,

Elevated pain sensitivity in chronic pain patients at risk for opioid misuse

No Opioids

Low-Dose Opioids

High-Dose Opioids

SOAPP = Screener and Opioid Assessment for Patients in Pain

Opioid exposure, OIH and post-operative pain

• Pre-operative chronic opioid use (i.e., OUD)

• Pre-operative acute opioid use (pre-emptive analgesia)

• Intra-operative opioid exposure and post-operative pain

• Intra-operative opioid exposure and chronic post-surgical pain

Suzan et al., 2018

“If present in central pain pathways at the time of tissue injury occurs, opioids augment acute post-injury (i.e., post-surgical) pain, in contrast to their analgesic effects when administered after tissue injury has ended.”

Pre-operative opioid use (4-8wks) augments post-operative pain

• Acute post-operative pain severity (both at rest or with walking)

• Post-surgical opioid consumption

• Length of hospitalization

• Rate of postoperative pain resolution

Suzan et al., 2018

Hina et al, 2015

Chronic pain patients on 42 + 25MME were hyperalgesic prior to orthopedic surgery, and used more pain medication and reported more severe pain 72 hourspostoperatively

Post-operative Pain Responses in Dental Patients on Chronic Opioid Therapy

Co-PIs Compton & Hersh

On >50MME opioids x 3 months

No opioid exposure

x 3 months

• oral surgical procedure with expected trauma rating of between 5 – 10

• prescribed NSAIDs for post-operative pain

Compare:• Pre-operative hyperalgesia (CP)• 72hr pain severity and

medication use (pain diary)

Post-operative Pain Responses in Dental Patients on Chronic Opioid Therapy

0

1

2

3

4

5

6

7

8

9

cold-pressor painseverity

heat thermode painseverity

VA

S P

ain

Rat

ing

Experimental Pain Severity Ratings (Preoperative)

not on opioids on opioids

0

1

2

3

4

5

6

7

8

6h

r

12

hr

18

hr

24

hr

30

hr

36

hr

42

hr

48

hr

54

hr

60

hr

66

hr

72

hr

VA

S p

ain

sev

erit

y

Pain Severity Ratings following Surgery

not on opioids on opioids

0 2 4 6 8 10

no. of doses

Number of Doses of Analgesics Taken (Postoperative)

on opioids not on opioids

Compton and Hersh, 2019

Pre-emptive analgesia for post-operative pain• Two large meta-analysis found no benefit for pre-emptive opioid treatment.

Moiniche et al., 2002; Ong et al., 2005

Pre-emptive opioid administration showed a trend toward enhancing rather than reducing postsurgical pain, as well as increasing analgesic consumption and decreasing time to rescue analgesic

Intra-operative opioids and OIH

Findings:

• Significantly higher post-operative pain scores at rest

• most pronounced early in post-op period, persists up to 24hr

• Most reliably demonstrated with high dose remifentanil

• More post-op morphine use in first 24hr (~18mg MS)

• Significantly decreased pain thresholds

• Larger area of wound hyperalgesia

• No difference in nausea, vomiting and drowsiness

Fletcher and Martinez, 2014

Meta-analysis of 127 studies involving 1494 patientsSurgeries included gynecologic, abdominal, C-section, cardiac, orthopedic, urologic, T&A, thyroidGeneral anesthesia maintained by inhalation agents or propofol infusionMost examined remifentanil or fentanylComparators were low dose or same agent and/or placebo

Implications forIntra-operative prevention of OIH

• Opioid-sparing strategies

• Not enough known about cumulative dose, duration of administration, opioid potency

• Keep continuous remifentanil infusions < 0.1 μg/kg/min or target-controlled infusion < 2.7 ng/ml

• Prevent with co-administration of ketamine, magnesium, propofol and nitrous oxide, clonidine

• Avoid with slow taper

• abrupt analgesic offset of remifentanil could be source of increased pain; bridge with a slower-acting opioid

Chronic Post-surgical Pain (CPSP)

• Population-based studies find 18% of patients who had surgery in past 3 years reported pain in area of surgery• 10.5% if exclude those who had same pain prior to surgery

• 6.2% if exclude those who had any pain prior to surgery

• ICD-11 diagnosis -• Develops or increases in intensity after a surgical procedure

• Persists beyond the healing process (> 3months)

• Localized to the surgical field or innervation territory of nerve located in surgical field

• Other causes of pain or pre-existing pain are excluded from CPSP diagnosis

• May be neuropathic pain, but should be classified as CPSP as opposed to neuropathic

Johansen et al., 2012; Schug et al, 2019

Schug & Bruce, 2017

Risk factors for developing CPSP

Eiseach & Brennan, 2018

Risk factors for developing CPSP

Eiseach & Brennan, 2018

Goesling et al., 2016

OIH - How do we measure it?

• Animal studies: hot plate, tail flick latency, paw withdrawal (heat, cold, mechanical)

• Across clinical studies: thermal (heat, cold), mechanical (pressure, touch, injection), electrical • Post-operative and normal control studies often used secondary or

wound pain.

• Early human studies focused on cold-pressor -> injection pain and heat pain intensity

• Settling on QST:• Conditioned pain modulation – supra-spinal systems • Temporal summation - spinal systems (wind-up)

• Spontaneous pain vs. evoked pain vs. wound hyperalgesia?

• Threshold vs. tolerance vs. self-rated severity?

OIH vs. Opioid Tolerance

Curve A - normal

Curve B - opioid-induced hyperalgesia (increased pain sensitivity, AB)

Curve C - tolerance (need more dose, AC)

Angst M, et al. . Anesthesiology 2006;104: 570-587.

In clinical practice they look the same

Withdrawal hyperalgesia

• In animal studies – hyperalgesia has historically been a symptom of opioid withdrawal

• Part of diagnostic criteria for opioid withdrawal syndrome• Severity worse with bolus dosing and agonist-precipitated

• For chronic pain patients, severity of pain at injury site greatly increases

• Opioid withdrawal hyperalgesia suspected in both normal control and post-operative samples:• Increase pain score

• Decrease pain threshold

• Increase wound hyperalgesia

• Increase opioid consumption/need

• Increased pain with higher dose and longer intra-operative exposure.

• Increased opioid consumption for cumulative dose > 50ug/kg

Angst M, Anesthes, 122(3), 677-85 2015

“Abrupt analgesic offset”

Differential Dx Nature

of pain Onset

Response to opioid

administration

Increased pain

pathology

Localized to pain site Variable Pain improves

Opioid tolerance Localized to pain site Gradual Pain improves

Opioid withdrawal Diffuse, hyperalgesia Abrupt Pain improves

Opioid-induced

hyperalgesia

Diffuse, hyperalgesia Abrupt or Gradual Pain worsens

Pseudo-addiction Localized to pain site Ongoing Pain improves

Addictive disease Diffuse, hyperalgesia Ongoing Pain worsens

Pain Characteristics and Opioid responses

Chronic Pain Opioid Therapy

Improved functioning Unimproved functioning

Addictive disease

+

opioid non-responsive pain

Psychiatric Illness

Opioid-induced hyperalgesia

Opioid-responsive pain

Absence of addiction

Psuedo-addiction

Therapeutic dependence

Compton et al, 2017

How do we treat it?

• Opioid sparing • Dose dependent, length of exposure

• Gradual opioid taper

• Opioid rotation• Methadone; buprenorphine

• Add adjuncts –• NMDA antagonists (ketamine, dextromethorphan)

• GABAminergic – Propofol, Gabapentin

• Anti-inflammatory agents - NSAIDS

*p=0.02, **p =0.01

***

*

*p=0.03

• 5-week RCT of gabapentin (titrated to 2400mg/day)

• Effects noted in subjects who abstained from illicit use

R01 DA05463, NIDA PI: Compton

OIH and OUD: Clinically-relevant research questions

• Does degree of OIH predict OUD outcomes?

• How does OIH complicate acute pain care for patients with OUD?

• Does OIH “set up” patients with OUD for the development of chronic pain?

• Can pain sensitivity in opioid naïve patients predict propensity to develop OUD? Or substance use disorder in general?

• Are the affective and cognitive components of pain also “upregulated” with chronic opioid use?

Selected References

Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology. 2006 104(3):570-87.

Chu LF, Clark DJ, Angst MS. Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: a preliminary prospective study. J Pain. 2006 Jan;7(1):43-8

Chu LF, Angst MS, Clark D. Opioid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations. Clin J Pain. 2008 Jul-Aug;24(6):479-96.

Compton P, Kehoe P, Sinha K, Torrington MA, Ling W. Gabapentin improves cold-pressor pain responses in methadone-maintained patients. Drug Alcohol Depend. 2010 Jun 1;109(1-3):213-9.

Compton, P.A., Ling, W., Torrington, M.A. Lack of Effect of Chronic Dextromethorphan on Experimental Pain Tolerance in Methadone-maintained Patients, Addiction Biology 13(3-4):393-402, 2008.

Compton, P., Athanasos, P., Elashoff, D., “Withdrawal Hyperalgesia After Acute Opioid Physical Dependence in Nonaddicted Humans: A Preliminary Study,” The Journal of Pain, 4(9): 511-519, 2003.

Compton P, Charuvastra VC, Kintaudi K, Ling w. Pain Responses in Methadone-Maintained Opioid Abusers Vol. 20 No. 4, 2000 Journal of Pain and Symptom Management 237

Compton, P., Charuvastra, V.C., and Ling, W., “Pain Intolerance in Opioid-Maintained Former Opiate Addicts: Effect of Long-Acting Maintenance Agent,” Drug Alcohol Depend., 63:139-146, 2001.

Doverty M, White JM, Somogyi AA, Bochner F, Ali R, Ling W. Hyperalgesic responses in methadone maintenance patients. Pain. 2001 Feb 1;90(1-2):91-6.

Doverty M, Somogyi AA, White JM, Bochner F, Beare CH, Menelaou A, Ling W.Methadone maintenance patients are cross-tolerant to the antinociceptiveeffects of morphine. Pain. 2001 Aug;93(2):155-63.

Hay JL, White JM, Bochner F, Somogyi AA, Semple TJ, Rounsefell B. Hyperalgesia in opioid-managed chronic pain and opioid-dependent patients. 2009 J Pain 10(3):316-22.

Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L. A comprehensive review of opioid-induced hyperalgesia. Pain Physician. 2011 Mar-Apr;14(2):145-61

Li X, Angst MS, Clark JD. A murine model of opioid-induced hyperalgesia. Brain Res Mol Brain Res. 2001 Jan 31;86(1-2):56-62.

Liang D, Liao G, Lighthall GK, Peltz G, Clark DJ. Genetic variants of the P-glycoprotein gene Abc1b modlte opioid induced hyperalgesia, tolearnce and dependence. Pharmacogenet Genomics. 200616(11):825-35

Mao J. Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy. Pain. 2002 Dec;100(3):213-7

Pud D, Cohen D, Lawental E, Eisenberg E. Opioids and abnormal pain perception: New evidence from a study of chronic opioid addicts and healthy subjects. Drug Alcohol Depend. 2006 May 20;82(3):218-23.