Efficacy, Safety, Tolerability and Pharmacokinetics of Concomitant Administration of Tramadol With Duloxetine or Pregabalin

Efficacy, Safety, Tolerability and Pharmacokinetics of Concomitant Administration of Tramadol With Duloxetine or Pregabalin: a Randomized Controlled Flexible-dose Study in Patients With Neuropathic Pain

Tramadol is an opioid analgesic, which is widely used in the treatment of acute and neuropathic pain. Treatment of neuropathic pain often requires a combination of pain medications due to the complex nature of neuropathic pain and frequent inadequate response to drug treatment. Common drugs used concomitantly with tramadol are SNRI antidepressant duloxetine and anticonvulsants such as pregabalin. Both tramadol and duloxetine have serotonergic effects and duloxetine has also a potential to inhibit metabolism of tramadol. The objective of the study is to investigate the pharmacokinetics and pharmacodynamic interaction of oral tramadol with duloxetine and pregabalin in patients with chronic neuropathic pain due to postherpetic neuralgia or diabetic polyneuropathy. All subjects will receive tramadol and duloxetine or tramadol and pregabalin in a randomized double-blind order. Primary end point is O-desmethyltramadol concentration.

Study Overview

• Status: Withdrawn
• Conditions: Diabetic Polyneuropathy; Postherpetic Neuralgia
• Intervention / Treatment: Drug: Tramadol; Drug: Duloxetine; Drug: Pregabalin

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• Finland
  • Turku, Finland, 20520
    • Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, Turku University and Turku University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Chronic (≥ 6 months) neuropathic pain due to postherpetic neuralgia or diabetic polyneuropathy
• Pain intensity ≥ 4 on a numerical scale of 0-10
• Informed consent

Exclusion Criteria:

• Clinically significant abnormalities in laboratory screening
• Pregnancy
• Depression
• Use of strong opioids (morphine, oxycodone, fentanyl, hydromorphone, methadone)
• A previous history of intolerance or allergy to the study drugs or to related compounds and additives
• Existing or history of seizures, haematological disorders, clinically significant renal, hepatic, respiratory, cardiac or psychiatric disease, dementia, drug allergy
• Previous or present alcoholism, drug abuse, psychological or other emotional problems or cognitive impairment that are likely to invalidate informed consent or limit the ability of the subject to comply with protocol requirements
• Concomitant drug therapy known to cause significant enzyme induction or inhibition of CYP 1A2, 2D6, 3A4, 2B6, drugs metabolised by CYP2D6 enzyme, antidepressants, MAO-inhibitors, non-steroidal anti-inflammatory analgesics.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Duloxetine and tramadol; To ascertain the double-blinding of subjects and investigators, duloxetine and pregabalin will be administered as 2 similar capsules twice a day. Each of these capsules will contain either 30mg of duloxetine, 75 mg of pregabalin or placebo. Capsules will be prepared at the hospital pharmacy.	Drug: Tramadol; Initial dose of oral tramadol (depottabl Tramal retard, Orionpharma, Finland) will be 100mg once daily. If the subject is currently on opioid treatment with codeine, tramadol or buprenorphine, the opioid treatment will be stopped, and an equal dose of tramadol will be used as the initial dose. The dose will be titrated on visits V2 and V3 based on the adequacy of pain relief and tolerability. If pain intensity ≥ 4 on a numeric rating scale of 0-10 during V2 and V3 and tramadol is well tolerated, the daily dose will be increased by 100mg. The maximum daily dose of 400 mg tramadol will not be exceeded. If the subject does not tolerate the initial dose of tramadol, he/she will be dropped out of the study and replaced by another patient.; Drug: Duloxetine; The initial dose of duloxetine (Cymbalta, Eli Lilly, USA) will be 30mg once daily. The dose will be titrated on V2 based on the adequacy of pain relief and tolerability. If pain intensity during V2 is < 4 on a scale of 0-10, the dose of duloxetine dose will be 30mg daily throughout the study. If pain intensity is ≥ 4 on a numeric rating scale of 0-10 and duloxetine is well tolerated, the daily dose will be increased to 60mg once daily. If the subject does not tolerate the initial dose of duloxetine, he/she will be dropped out of the study and replaced by another patient.
Active Comparator: Pregabalin and tramadol; To ascertain the double-blinding of subjects and investigators, duloxetine and pregabalin will be administered as 2 similar capsules twice a day. Each of these capsules will contain either 30mg of duloxetine, 75 mg of pregabalin or placebo. Capsules will be prepared at the hospital pharmacy.	Drug: Tramadol; Initial dose of oral tramadol (depottabl Tramal retard, Orionpharma, Finland) will be 100mg once daily. If the subject is currently on opioid treatment with codeine, tramadol or buprenorphine, the opioid treatment will be stopped, and an equal dose of tramadol will be used as the initial dose. The dose will be titrated on visits V2 and V3 based on the adequacy of pain relief and tolerability. If pain intensity ≥ 4 on a numeric rating scale of 0-10 during V2 and V3 and tramadol is well tolerated, the daily dose will be increased by 100mg. The maximum daily dose of 400 mg tramadol will not be exceeded. If the subject does not tolerate the initial dose of tramadol, he/she will be dropped out of the study and replaced by another patient.; Drug: Pregabalin; The initial dose of pregabalin (Lyrica, Pfizer, USA) will be 75mg twice a day. The dose will be titrated on V2 based on the adequacy of pain relief and tolerability. If pain intensity during V2 is < 4 on a scale of 0-10, the initial dose of pregabalin dose will be continued. If pain intensity is ≥ 4 on a numeric rating scale of 0-10 and pregabalin is well tolerated, the daily dose will be increased to 150mg twice a day. If the subject does not tolerate the initial dose of pregabalin, he/she will be dropped out of the study and replaced by another patient.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Concentration of O-desmethyltramadol	3 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma 5-HT concentration		baseline, 1, 2 and 3 weeks
Platelet function		baseline and 3 weeks
Pain intensity	Pain intensity will be rated by the subjects on a numerical 11-point rating scale of 0-10 (NRS) with 0 meaning "no pain" and 10 meaning "pain as bad as you can imagine". The subjects will be asked to rate pain intensity on the average over the past 24 hours. Pain intensity will be recorded at each study visit and daily by the subject using a pain diary.	daily for 3 weeks
Use of rescue medication		1,2 and 3 weeks
Behavioral serotonergic effects		1, 2 and 3 weeks
Concentration of O-desmethyltramadol		baseline, 1 and 2 weeks

Collaborators and Investigators

• Sponsor: Turku University Hospital
• Collaborators: University of Helsinki
• Investigators: Principal Investigator: Klaus T Olkkola, MD,PhD,Prof, Turku University Hospital and Turku University

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (Actual): December 1, 2012
• Study Completion (Anticipated): December 1, 2012

Study Registration Dates

• First Submitted: April 19, 2010
• First Submitted That Met QC Criteria: May 3, 2010
• First Posted (Estimate): May 5, 2010

Study Record Updates

• Last Update Posted (Estimate): May 31, 2013
• Last Update Submitted That Met QC Criteria: May 30, 2013
• Last Verified: May 1, 2013

More Information

Terms related to this study

• Keywords: Pharmacokinetics; pregabalin; Pharmacodynamics; duloxetine; tramadol; Interaction
• Additional Relevant MeSH Terms: Nervous System Diseases; Pain; Neurologic Manifestations; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Neuromuscular Diseases; Peripheral Nervous System Diseases; Neuralgia; Polyneuropathies; Diabetic Neuropathies; Neuralgia, Postherpetic; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Anti-Anxiety Agents; Anticonvulsants; Serotonin and Noradrenaline Reuptake Inhibitors; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Duloxetine Hydrochloride; Pregabalin; Tramadol
• Other Study ID Numbers: 60/180/2009

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No