Opioid Induced Hyperalgesia (OIH): 

Cold Pressor Test (CPT)

The cold pressor test (CPT) is a standardized, practical method for assessing pain sensitivity and tolerance

 

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Definitions and Terms Related to Pain

Cold Pressor Test (CPT)

The cold pressor test (CPT) is a standardized, practical method for assessing pain sensitivity and tolerance in patients receiving chronic opioid therapy, and is commonly used to help identify opioid-induced hyperalgesia (OIH) in clinical and research settings.

How the cold pressor test is performed:

– Preparation: Fill a container with ice water, maintaining the temperature at approximately 1–4°C (ideally 1°C for maximal sensitivity).[1][2][3]

– Procedure: Ask the patient to immerse their non-dominant hand (usually up to the wrist) into the ice water.

– Assessment: Instruct the patient to keep their hand submerged for as long as possible, but to withdraw it immediately when the pain becomes intolerable.

– Measurements: Record two key metrics:

– Pain threshold: Time (in seconds) until the patient first reports feeling pain.

– Pain tolerance: Time (in seconds) until the patient withdraws their hand due to intolerable pain.

– Safety: Maximum immersion time is typically capped at 120 seconds to prevent tissue injury.[2][3]

 

Interpretation for OIH:

– Patients with OIH typically show lower pain tolerance and threshold compared to opioid-naïve controls (e.g., mean tolerance 18–20 seconds vs. 30+ seconds in controls).[2][3]

– The CPT is sensitive to changes in pain processing associated with chronic opioid exposure and is validated in both clinical and research populations.[4][2][3]

– The test can be repeated over time to monitor changes in pain sensitivity, especially after opioid dose adjustments or interventions such as opioid rotation or naltrexone therapy.[5][3]

 

Clinical notes:

– The CPT is easy to administer and provides objective, reproducible data on pain sensitivity.

– It is most useful when combined with clinical assessment and other sensory testing modalities, as OIH may not affect all pain modalities equally.[4][6]

– The CPT does not typically induce allodynia, but is a reliable marker for hyperalgesia in opioid-managed patients.[2][3]

 

Summary:

To assess for OIH in chronic opioid patients, the cold pressor test is performed by immersing the hand in ice water, measuring pain threshold and tolerance, and comparing results to normative values or baseline. Lower pain tolerance is suggestive of OIH, especially when correlated with clinical findings and other sensory tests.

 

Normal values and reference ranges for CPT results in opioid-naïve versus opioid-treated populations

Normal cold pressor test values differ substantially between opioid-naïve individuals and those treated with chronic opioids, with opioid-treated patients consistently showing lower pain tolerance and threshold.

  • Healthy controls (opioid-naïve) typically have a mean cold pain threshold of 15 seconds and a mean pain tolerance of 69 seconds.
  • Patients treated with chronic opioids (including methadone or morphine for pain or opioid use disorder) show a mean cold pain threshold of 10–12 seconds and a mean pain tolerance of 18–29 seconds—about half or less than that of controls.[1][2][3][4]

For example, mean cold pressor tolerance values of 18.1 ± 2.6 seconds (morphine), 19.7 ± 2.3 seconds (methadone for pain), and 18.9 ± 1.9 seconds (methadone maintenance for dependence), all significantly lower than opioid-naïve subjects (30.7 ± 3.9 seconds).[1]

 

Reference ranges of average tolerances with CPT:

  • Untreated patients seeking opioid use disorder treatment:  22 seconds
  • Patients on chronic opioid treatment: 29 seconds
  • Healthy controls: 69 seconds
  • abstinent patients: 77 seconds
  • antagonist-treated (naltrexone) patients: 96 seconds[2]

 

Key reference ranges:

  • – Opioid-naïve controls: Threshold ~15 sec, Tolerance ~69 sec
  • – Chronic opioid-treated (pain or OUD): Threshold ~10–12 sec, Tolerance ~18–29 sec

These differences are robust across multiple studies.

 

Summary

Chronic opioid therapy is associated with a marked reduction in cold pressor pain tolerance and threshold compared to opioid-naïve individuals, supporting the use of the cold pressor test as an objective marker for opioid-induced hyperalgesia in clinical practice.

 

Does pain sensitivity decrease after opioid tapering or discontinuation in patients with chronic pain treated with long-term opioids

Cold pressor test (CPT) results generally improve—meaning pain sensitivity decreases—after opioid tapering or discontinuation in patients with chronic pain treated with long-term opioids, but normalization of pain sensitivity may be incomplete or delayed, and findings vary by study design and patient population.

Key findings:

Improvement after opioid discontinuation:

In a case series of opioid-maintained chronic pain patients, mean CPT times (pain tolerance) increased for 90% of patients after one month of abstinence, indicating improved pain tolerance. Baseline CPT was 48 seconds for opioid-maintained patients versus 102 seconds for controls, and most patients reported stable or improved pain after detoxification. This suggests that opioid-induced hyperalgesia (OIH) is at least partially reversible with opioid cessation, and pain sensitivity as measured by CPT improves over weeks.[1]

Incomplete or delayed normalization:

Other studies show that pain sensitivity may not fully normalize within the first month after opioid discontinuation. In a study of opioid addicts undergoing a 4-week detoxification, CPT measures (pain threshold, intensity, and tolerance) did not significantly change over 28 days, remaining lower than healthy controls. This suggests that OIH may persist for at least several weeks after stopping opioids.[2]

Meta-analytic evidence:

Systematic reviews and meta-analyses confirm that chronic opioid exposure is associated with reduced cold pain tolerance (i.e., increased pain sensitivity) compared to opioid-naïve controls. However, pooled data indicate that cold pain threshold, tolerance, and intensity do not significantly differ between abstinent patients and healthy controls, nor between abstinent patients and those on opioid agonist treatment, when abstinence is prolonged.[3] This supports the idea that pain sensitivity can normalize over time, but the timeline is variable and may require extended abstinence.

Short-term effects of tapering:

In a small study of chronic pain patients undergoing rapid opioid tapering (7–14 days), greater opioid reduction was paradoxically associated with decreased pain tolerance (i.e., increased pain sensitivity) immediately after withdrawal, not improvement. This acute increase in pain sensitivity may reflect withdrawal-related hyperalgesia, which can resolve with longer abstinence.[4]

 

Summary Table: Cold Pressor Test Changes After Opioid Taper/Discontinuation

Study/Review

Timeline After Discontinuation

CPT Change (Pain Tolerance)

Normalization vs Controls

Notes

Belkin et al [1]

1 month

↑ (improved in 90%)

Not fully normalized

Most reported stable/improved pain

Pud et al [2]

4 weeks

No significant change

Remained lower

OIH persists at 1 month

Trøstheim et al [3]

Prolonged abstinence

No significant difference

Normalizes over time

Meta-analysis, variable timeline

Younger et al [4]

7–14 days (rapid taper)

↓ (decreased tolerance)

Not normalized

Acute withdrawal effect

Summary:

Pain sensitivity as measured by the cold pressor test generally improves after opioid tapering or discontinuation, but may not fully normalize for several weeks to months. Some patients experience persistent hyperalgesia for at least a month, while meta-analytic data suggest normalization with prolonged abstinence. Acute withdrawal may temporarily worsen pain sensitivity.

 

References – The cold pressor test (CPT)

  1. Oral Opioid Use Alters DNIC but Not Cold Pain Perception in Patients With Chronic Pain – New Perspective of Opioid-Induced Hyperalgesia. Ram KC, Eisenberg E, Haddad M, Pud D. Pain. 2008;139(2):431-438. doi:10.1016/j.pain.2008.05.015.
  2. Hyperalgesia in Opioid-Managed Chronic Pain and Opioid-Dependent Patients. Hay JL, White JM, Bochner F, et al. The Journal of Pain. 2009;10(3):316-22. doi:10.1016/j.jpain.2008.10.003.
  3. Opioid Tolerance and Hyperalgesia in Chronic Pain Patients After One Month of Oral Morphine Therapy: A Preliminary Prospective Study. Chu LF, Clark DJ, Angst MS. The Journal of Pain. 2006;7(1):43-8. doi:10.1016/j.jpain.2005.08.001.
  4. Evidence of Opioid-Induced Hyperalgesia in Clinical Populations After Chronic Opioid Exposure: A Systematic Review and Meta-Analysis. Higgins C, Smith BH, Matthews K. British Journal of Anaesthesia. 2019;122(6):e114-e126. doi:10.1016/j.bja.2018.09.019.
  5. The Effects of Low Dose Naltrexone on Opioid Induced Hyperalgesia and Fibromyalgia. Jackson D, Singh S, Zhang-James Y, Faraone S, Johnson B. Frontiers in Psychiatry. 2021;12:593842. doi:10.3389/fpsyt.2021.593842.
  6. Review of the Performance of Quantitative Sensory Testing Methods to Detect Hyperalgesia in Chronic Pain Patients on Long-Term Opioids. Katz NP, Paillard FC, Edwards RR. Anesthesiology. 2015;122(3):677-85. doi:10.1097/ALN.0000000000000530.

 

References – Normal cold pressor test values

  1. Hyperalgesia in Opioid-Managed Chronic Pain and Opioid-Dependent Patients. Hay JL, White JM, Bochner F, et al. The Journal of Pain. 2009;10(3):316-22. doi:10.1016/j.jpain.2008.10.003.
  2. Hyperalgesia in Patients With a History of Opioid Use Disorder: A Systematic Review and Meta-Analysis. Trøstheim M, Eikemo M. JAMA Psychiatry. 2024;81(11):1108-1117. doi:10.1001/jamapsychiatry.2024.2176.
  3. Opioids and Abnormal Pain Perception: New Evidence From a Study of Chronic Opioid Addicts and Healthy Subjects. Pud D, Cohen D, Lawental E, Eisenberg E. Drug and Alcohol Dependence. 2006;82(3):218-23. doi:10.1016/j.drugalcdep.2005.09.007.
  4. Ameliorative Response to Detoxification, Psychotherapy, and Medical Management in Patients Maintained on Opioids for Pain. Belkin M, Reinheimer HS, Levy J, Johnson B. The American Journal on Addictions. 2017;26(7):738-743. doi:10.1111/ajad.12605.

 

References – Pain Sensitivity Recovery

  1. Ameliorative Response to Detoxification, Psychotherapy, and Medical Management in Patients Maintained on Opioids for Pain. Belkin M, Reinheimer HS, Levy J, Johnson B. The American Journal on Addictions. 2017;26(7):738-743. doi:10.1111/ajad.12605.
  2. Opioids and Abnormal Pain Perception: New Evidence From a Study of Chronic Opioid Addicts and Healthy Subjects. Pud D, Cohen D, Lawental E, Eisenberg E. Drug and Alcohol Dependence. 2006;82(3):218-23. doi:10.1016/j.drugalcdep.2005.09.007.
  3. Hyperalgesia in Patients With a History of Opioid Use Disorder: A Systematic Review and Meta-Analysis. Trøstheim M, Eikemo M. JAMA Psychiatry. 2024;81(11):1108-1117. doi:10.1001/jamapsychiatry.2024.2176.
  4. Reduced Cold Pain Tolerance in Chronic Pain Patients Following Opioid Detoxification. Younger J, Barelka P, Carroll I, et al. Pain Medicine (Malden, Mass.). 2008;9(8):1158-63. doi:10.1111/j.1526-4637.2008.00475.x.

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