# Presentation: 207113

## Opioid Tolerance and Opioid-Induced Hyperalgesia

- David J. Clark

## Chronic Opioid Use: Long-Term Difficulties

- _Loss of Effect_
- Advancing disease
**Analgesic tolerance**
**Hyperalgesia**

- _Creation of Problems_
- Side Effects
- CNS
- Gastrointestinal
- Sweating
- Physical Dependence
- Abuse, Addiction

## Opioid Tolerance(Does it matter?)

- Tolerance is relevant?
- Clinicians
- Bhamb et al. 2006, 61% of primary care physicians concerned about tolerance occurring when managing chronic pain
- Researchers, Clinical and Basic (~5500 publications, key words “opioid tolerance”)
- Drug manufacturers, “Black Box” warnings
- Tolerance is irrelevant?
- “Pharmacological tolerance is not a significant determinant of opioid dosing requirements.” South and Smith, 2001
- “ In terms of analgesic efficacy, clinically significant tolerance does not seem to be an issue for acute or cancer pain or in most patients with chronic pain.” Auret and Schug, 2005

## Analgesic Tolerance vs. Opioid-Induced Hyperalgesia

## Analgesic Tolerance

- Pharmacokinetic etiologies
- Quantities and ratios of morphine and major metabolites (M6G, M3G)
- Pharmacodynamic etiologies
- Receptor density, efficiency
- Second messenger system alterations
- Target “effector” molecule alterations
- Diminished activity of antinociceptive circuits
- Enhanced activity of pronociceptive circuits

## Human Opioid Tolerance(Direct Studies, Chronic)

- Athanasos et al. 2006

**Notes:**
Also, there was no dose dependence to effects for patients maintained on 11-115mg/day methadone

Targets roughly 11 and 33 ng/ml for naïve patients.

Postoperative pain relief for mod/severe pain may require 50 ng/ml.

## Human Opioid Tolerance(Direct Studies, Chronic)

- Chu et al., 2006

## Human Opioid Tolerance(Direct Studies, Acute)

- Vinik et al. 1998

- _Model: Cold Pressor_

## Human Opioid Tolerance(Direct Studies, Acute)

- Gustorff et al., Anesth Analg 2002

## Human Opioid Tolerance(Indirect Studies)

- Rapp et al. 1995
- 180 Control/180 CPOC patients having surgery
- Average CPOC pre-op daily parenteral morphine equivalent use 12.7mg
- Average Daily PCA Morphine
- _Control_			_CPOC_
**42.8mg****	****	****	****135.8mg**
- CPOC pain scores were worse despite larger morphine use.
- Greater side effects including sedation (50%) in CPOC group
- On-service approximately 3 times as long

## Human Opioid Tolerance(Indirect Studies)

- de Leon-Casasola et al., 1993
- 99 Control, 17 CPOC patients having major surgery
- Average pre-op opioid use 183mg
- Epidural bupivacaine/morphine post-op management
- Total epidural MSO4: 	137 vs. 44mg	(CPOC vs. Control)
- Total IV breakthrough:	48 vs. 10mg
- Length of therapy:	218 vs. 76 hrs

## Human Opioid Tolerance(Indirect Studies)

- _Supporting_
- Crawford et al. 2006
- Remifentanil vs. Morphine
- Guignard et al. 2000
- Remifentanil
- Chia et al. 1999
- Fentanyl
- Cooper et al. 1997
- Intrathecal fentanyl

- _Refuting_
- Cortinez et al. 2001
- Remifentanil
- Hansen et al. 2005
- Remifentanil/Epidural
- Higher 2 hr pain scores

- Intraoperative opioid administration versus postoperative opioid consumption

## Human Opioid Tolerance(Indirect Studies)

- Rainov et al., 2001

- Intrathecal morphine dose escalation in patients with FBSS

**Notes:**
Williams et al. (2004) tabulated dose escalation of between 1 and 160%/week in a panel of studies which was partially due to the duration of the study. More modest dose increases were noted after about the first year of therapy. It is unclear what portion of the dose increase was titration to effect, and what was tolerance.

Some say ongoing dose increase is due to the nearly futile attempt to treat remaining non-opioid responsive pain. 

## Human Opioid Tolerance(Indirect Studies)

- Milligan et al., 2001

- Fentanyl dose escalation in patients with chronic non-malignant pain

## Opioid Dose Escalation and Tolerance(Factors Involved)

- _Increasing Doses_
- Advancing disease
- Tolerance
**Hyperalgesia**

- _Limiting Doses_
- Better controlled pain
- Side effects
- Lack of efficacy
- Fear of addiction
- Cost
- Stigmatization

## Tolerance vs. Hyperalgesia

## Opioid-Induced Hyperalgesia(Historical perspective)

- “when dependence on opioids finally becomes an illness of itself, opposite effects like restlessness, sleep disturbance, hyperasthesia, neuralgia and irritability become manifest”

- Rossbach, Pflugers Archieve 1880

- Opioid-Induced Hyperalgesia(Historical perspective)

**Notes:**
For more than a century, clinical reports have listed hyperestesia, or an increased sensitivity to pain as one of the symptoms associated with opioid withdrawal:
Rossbach observed that patients on a chronic dose of morphine or withdrawing form morphine showed signs quite different from those associated with acute opioid intoxication. 

## Opioid-Related Hyperalgesia(Direct Studies, Chronic)

- Doverty et al., 2001

## Opioid-Related Hyperalgesia(Direct Studies, Chronic)

- Chu, Clark and Angst; J Pain 2006

## Opioid-Related Hyperalgesia(Direct Studies, Acute)

- Koppert et al. 2003

- Remi (30min)

- Remi (30min)

- Model: Electrical Pain/Hyperalgesia

## Opioid-Related Hyperalgesia(Direct Studies, Acute)

- Hood et al. 2003

- Model: Heat/Capsaicin

## Opioid-Related Hyperalgesia(Direct Studies, Acute)

- Compton,  Journal of Pain 2003

**Notes:**
Volunteers undergoing precipitated withdrawal with naloxone 10 mg/70kg 2 hours after 10 mg morphine or 2 mg hydromorphone IV showed signs of hyperalgesia in CPT. Hyperalgesia was accompanied by other signs of withdrawal: elevation in HR, BP, RR, restlessness, irritability and hot/cold feelings.

## Opioid-Related Hyperalgesia(Direct Studies, Acute)

- Angst et al., Pain 2003

## Opioid-Related Hyperalgesia(Direct Studies, Chronic)

- Galer et al., 2005

**Notes:**
300 patients with OA. Run-in on morphine then re-start at 50% dose. Approximate 40% drop rate from lack of efficacy and side effects.

## Opioid-Related Hyperalgesia(Direct Studies, Acute)

- Koppert et al., 2006

## Tolerance and Opioid-Induced Hyperalgesia:What should we do in clinic?

- Inform:
- Tolerance and hyperalgesia may reduce the efficacy of therapy.
- More pain might be experienced during or after surgical procedures.
- Follow:
- Pain control, dose escalation
- Distribution of pain
- Consider:
- Detoxification in certain circumstances

## Perioperative Management of Opioid Consuming Patients

- Preoperative
- Identify, quantify, stabilize, collaborate
- Intraoperative
- Opioids: doses, short versus long acting
- Adjuvants: NSAIDS, ketamine, alpha-2, etc.
- Regional anesthesia
- Postoperative
- Opioids, adjuvants, regional analgesia
- Transition planning

## Tolerance and Opioid Related Hyperalgesia:Perioperative Management

- Carroll, I.R., M.S. Angst, and J.D. Clark, *Management of perioperative pain in patients chronically consuming opioids.* Reg Anesth Pain Med, 2004. **29**(6): p. 576-91.
- de Leon-Casasola, O.A., *Cellular mechanisms of opioid tolerance and the clinical approach to the opioid tolerant patient in the post-operative period.* Best Pract Res Clin Anaesthesiol, 2002. **16**(4): p. 521-5.
- 3.	Mitra, S. and R.S. Sinatra, *Perioperative management of acute pain in the opioid-dependent patient.* Anesthesiology, 2004. **101**(1): p. 212-27.

## Thank You