Increased Sensitivity to Pain Caused by Opioids in People Who Have Abused Prescription Opioids

Chronic Pain Clinical Trial

Official title:

Opioid-Induced Hyperalgesia in Prescription Opioid Abusers: Effects of Pregabalin

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01821430
• Other study ID #: Pro00000669
• Secondary ID: U01DA029580
• Status: Terminated
• Phase: Phase 2
• First received: March 27, 2013
• Last updated: February 7, 2017
• Start date: March 2013
• Est. completion date: February 2016

Study information

• Verified date: February 2017
• Source: Georgetown University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Managing pain in patients who abuse prescription opioids presents many challenges, including the development of opioid-induced hyperalgesia (OIH). Hyperalgesia is a condition in which something that usually feels slightly painful is perceived as something very painful. The proposed study will test the efficacy of the well-known neurological medication pregabalin to diminish OIH and chronic pain in persons who are in Suboxone (buprenorphine) or methadone treatment for prescription drug abuse.

Description:

The clinical management of pain in prescription opioid abusers presents a challenge to the health care professional. Investigators have novel pilot data showing that the GABA-agonist gabapentin (GPN) significantly decreases opioid-induced hyperalgesia (OIH) in methadone patients (Compton et al., 2009), providing the first empirical evidence of a pharmacotherapy for OIH in opioid abusers. The work of Gore and colleagues (2011) showed that pregabalin (PGB), a GABA analogue succeeding GPN, was shown to decrease opioid use in patients with neuropathic pain in patients, suggesting an anti-hyperalgesia effect not observed in the matched cohort receiving GPN. The proposed research will comprehensively evaluate the efficacy of PGB in treating opioid-induced hyperalgesia (OIH) in a well-described population of prescription opioid abusers (POAs) with chronic pain and on Suboxone (buprenorphine) or methadone therapy. A pressing need for such investigation is presented by the rising number of POAs presenting for treatment (SAMHSA, 2010; 2011), and for whom, chronic pain is a common co-morbidity. The proposed work is anticipated to provide vital and timely information on the efficacy of PGB in the treatment of OIH in prescription opioid abusers on Suboxone or methadone therapy.

Following recruitment and screening, 75 subjects assigned to the active medication group will receive pregabalin 400 mg/day, a dose well-within published guidelines of 300-600 mg/day for the treatment of neuropathic pain (http://www.pfizerpro.com/hcp/lyrica/phndosing). During the first week of treatment, subjects will be quickly titrated up to the assigned daily PGB dose of 400 mg/day PO (50mg BID x 2 days; 100mg BID x 2 days; 150mg BID x 2 days, with full dosage of 400mg administered on day 7 ), or maximum dose tolerated) for six weeks. 75 subjects will be assigned to receive matched and undergo identical titration and study activities under double-blind conditions. Study staff will evaluate subjects daily by phone during titration; thereafter they will be seen weekly at study sessions. Tapering of medication will begin at the end of week 6. The severity of chronic pain will be measured at each time point using two standardized self report tools which report on pain severity (McGill Pain Questionnaire) and pain-related disability (Brief Pain Inventory). Opioid-induced hyperalgesia will be measured at each time point using a standardized cold pressor trial, and performance at baseline will be compared to performance following PGB/placebo administration over time.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 4
• Est. completion date: February 2016
• Est. primary completion date: February 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years to 65 Years

Eligibility

Inclusion Criteria:

1. Be between the ages of 21 and 65 years of age.

2. Have a DSM-IVR diagnosis (used through 10/1/2014) of prescription opioid abuse or dependence disorder or a DSM-5 diagnosis of opioid use disorder.

3. Be enrolled and compliant in Suboxone or methadone treatment and on a stable dose [Suboxone (6-24mg/day); of methadone (60-120mg/day)] x at least 10 days.

4. Provide urine sample absent of any non-prescribed drugs of abuse at screening.

5. Screening cold-pressor pain tolerance < 70 seconds

6. Have chronic lower back pain or arthritis pain (duration six or more months).

7. Be otherwise in good physical health, or in the case of a medical condition needing ongoing treatment, be in the care of a physician who is willing to take responsibility for such treatment. The same conditions apply in cases of patients with a psychiatric disorder needing ongoing treatment.

8. Be agreeable to and capable of signing an informed consent.

Exclusion Criteria:

1. Have known sensitivity to pregabalin or gabapentin.

2. Potential participants must not be taking the following medications: pregabalin or gabapentin, tiagabine, vigabatrin, valproate, phenobarbital or primidone for the treatment of epilepsy; SNRI or TCA antidepressants; baclofen; or carbamazepine, oxycarbazepine or lamotrigine for the treatment of chronic pain.

3. Currently be substance dependent on alcohol, benzodiazepine, methamphetamine, cocaine or other drugs of abuse (except nicotine).

4. Have any acute medical condition that would make participation medically hazardous, (e.g., acute hepatitis, unstable cardiovascular disease, liver or renal disease) or have liver enzyme values (AST or ALT) greater than 5 times normal range.

5. Be acutely psychotic, severely depressed and in need of inpatient treatment, or an immediate suicide risk.

6. Have a neurological or psychiatric illness (i.e., schizophrenia, Raynaud's disease, urticaria, stroke) that would affect pain responses.

7. Be currently taking opioid analgesic medication for a painful condition on a regular basis.

8. Be a nursing or pregnant female, or a female or male who does not agree to not become pregnant or father a child during the course of, and six months following completion of the study. If a subject becomes pregnant or fathers a child during the study, they must immediately notify the study investigator.

9. Have a history of heart disease, stroke, liver or kidney disease, epilepsy or acute hepatitis, or currently have a pacemaker or uncontrolled high blood pressure.

Related Conditions & MeSH terms

• Chronic Pain

Intervention

Drug:
• Pregabalin
Titration of intervention will begin with 50mg PO BID x 2 days, then 100mg PO BID x 2 days, then 150mg PO BID X 2 days, then on day 7 full dose of Pregabalin 400mg PO QD for six weeks
• Placebo
Placebo group will follow the same titration as the pregabalin group

Locations

Country	Name	City	State
United States	Georgetown University	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Georgetown University	National Institute on Drug Abuse (NIDA)

Country where clinical trial is conducted

United States, 

References & Publications (19)

Backonja MM. Anticonvulsants (antineuropathics) for neuropathic pain syndromes. Clin J Pain. 2000 Jun;16(2 Suppl):S67-72. Review. — View Citation

Barrett AC, Smith ES, Picker MJ. Capsaicin-induced hyperalgesia and mu-opioid-induced antihyperalgesia in male and female Fischer 344 rats. J Pharmacol Exp Ther. 2003 Oct;307(1):237-45. — View Citation

Ben-Menachem E. Pregabalin pharmacology and its relevance to clinical practice. Epilepsia. 2004;45 Suppl 6:13-8. Review. — View Citation

Blitz B, Dinnerstein AJ, Lowenthal M. Performance on the pain apperception test and tolerance for experimental pain: a lack of relationship. J Clin Psychol. 1968 Jan;24(1):73. — View Citation

Bodian D. Origin of specific synaptic types in the motoneuron neuropil of the monkey. J Comp Neurol. 1975 Jan 15;159(2):225-43. — View Citation

Chen AC, Dworkin SF, Haug J, Gehrig J. Human pain responsivity in a tonic pain model: psychological determinants. Pain. 1989 May;37(2):143-60. Review. Erratum in: Pain 1989 Nov;39(2):248. — View Citation

Chéry-Croze S. Relationship between noxious cold stimuli and the magnitude of pain sensation in man. Pain. 1983 Mar;15(3):265-9. — View Citation

Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore. 1994 Mar;23(2):129-38. Review. — View Citation

Compton P, Charuvastra VC, Ling W. Pain intolerance in opioid-maintained former opiate addicts: effect of long-acting maintenance agent. Drug Alcohol Depend. 2001 Jul 1;63(2):139-46. — View Citation

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. doi: 10.1016/j.drugalcdep.2010.01.006. — View Citation

Compton PA, Ling W, Torrington MA. Lack of effect of chronic dextromethorphan on experimental pain tolerance in methadone-maintained patients. Addict Biol. 2008 Sep;13(3-4):393-402. doi: 10.1111/j.1369-1600.2008.00112.x. — View Citation

Gore M, Tai KS, Zlateva G, Bala Chandran A, Leslie D. Clinical characteristics, pharmacotherapy, and healthcare resource use among patients with diabetic neuropathy newly prescribed pregabalin or gabapentin. Pain Pract. 2011 Nov-Dec;11(6):528-39. doi: 10.1111/j.1533-2500.2011.00450.x. — View Citation

Hansen GR. The drug-seeking patient in the emergency room. Emerg Med Clin North Am. 2005 May;23(2):349-65. Review. — View Citation

Holtman JR Jr, Wala EP. Characterization of the antinociceptive and pronociceptive effects of methadone in rats. Anesthesiology. 2007 Mar;106(3):563-71. — View Citation

Ifuku M, Iseki M, Hidaka I, Morita Y, Komatus S, Inada E. Replacement of gabapentin with pregabalin in postherpetic neuralgia therapy. Pain Med. 2011 Jul;12(7):1112-6. doi: 10.1111/j.1526-4637.2011.01162.x. — View Citation

Paulson MR, Dekker AH, Aguilar-Gaxiola S. Eliminating disparities in pain management. J Am Osteopath Assoc. 2007 Sep;107(9 Suppl 5):ES17-20. — View Citation

Ramanujam VM, Anderson KE, Grady JJ, Nayeem F, Lu LJ. Riboflavin as an oral tracer for monitoring compliance in clinical research. Open Biomark J. 2011;2011(4):1-7. — View Citation

Tassone DM, Boyce E, Guyer J, Nuzum D. Pregabalin: a novel gamma-aminobutyric acid analogue in the treatment of neuropathic pain, partial-onset seizures, and anxiety disorders. Clin Ther. 2007 Jan;29(1):26-48. Review. — View Citation

Tassorelli C, Micieli G, Osipova V, Rossi F, Nappi G. Pupillary and cardiovascular responses to the cold-pressor test. J Auton Nerv Syst. 1995 Oct 5;55(1-2):45-9. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Improved Pain Response, threshold and tolerance	To test the efficacy of PGB, compared to placebo, to diminish OIH, as evidenced by improved pain responses (threshold and tolerance) to experimentally induced cold-pressor pain, in a well-described sample of POA patients with chronic pain and on buprenorphine or methadone therapy.; Pain Threshold: On the CP assay, pain threshold is operationalized as the number of seconds after the onset of the painful stimulus when a painful sensation is first detected. Subjects will indicate threshold by saying "Pain."; Pain Tolerance: On the CP assay, pain tolerance is operationalized as the number of seconds after the onset of the painful stimulus when the painful sensation is subjectively intolerable. Subjects will indicate tolerance by removing their arm from the ice bath.	8 weeks
Secondary	Improvement in pain severity and daily functionality	To test the efficacy of PGB, compared to placebo, to diminish chronic pain, as evidenced by improvements in pain severity and functionality in a well-described sample of POA patients with chronic pain and on buprenorphine or methadone therapy.; Pain Severity will be measured with The McGill Pain Questionnaire. Daily Functionality will be measured with the Brief Pain Inventory	8 weeks