Abstract: Efficacy and Safety of a Tramadol/Acetaminophen Combination (Ultracet™) in the Management of Fibromyalgia Related Pain: A Multicenter, Outpatient, Randomized, Double-Blind, Placebo-Controlled Study

Objective: To evaluate the efficacy and safety of a new combination analgesic tablet, tramadol/acetaminophen (APAP), for the treatment of pain in fibromyalgia (FM) patients. It is hypothesized that both tramadol and acetaminophen influence spinal inhibitory nociceptive pathways, suggesting that this combination is a promising therapy for central pain states.

Methods: This was a 91 day, multi-center outpatient study comparing the efficacy of tramadol and APAP (37.5 mg/325 mg) tablets to placebo in the management of FM pain. All subjects fulfilled the 1990 ACR classification criteria for FM and had no other significant pain condition. The study employed a parallel, randomized, double-blind, placebo-controlled design. Following an analgesic washout of up to 3 weeks, patients were randomly assigned to either tramadol/APAP or placebo and titrated by 1 tablet every 3 days to a total of 4 tablets/day on Day 10. Thereafter, dose was adjusted as needed to a maximum of 8 tablets/day. The primary outcome variable was time to discontinuation due to insufficient pain relief (Kaplan-Meier analysis). Secondary measures were final pain visual analog (PVA) scores, final pain relief scores, tender-point scores, and fibromyalgia impact questionnaire (FIQ) scores.

Results: A total of 313 patients (94% female, mean age 50) were randomized to tramadol/APAP (n = 156) or placebo (n = 157). Kaplan-Meier estimates of cumulative discontinuation rates due to insufficient pain relief were consistently lower in the tramadol/APAP group (P < .001). Final estimates of cumulative discontinuation rates were 28.1% for tramadol/APAP and 50.8% for placebo (P < .001). Tramadol/APAP patients had significantly better final PVA scores (P <.001), final pain relief scores (P < .001), total tender points scores (P = .040), and total FIQ scores (P = .008). Adverse event discontinuation occurred in 18.6% of tramadol/APAP and 11.5% of placebo patients. The most common adverse events in the tramadol/APAP group were nausea, headache, and pruritis. The average dose of tramadol/APAP was 4.0 tablets/day. Conclusion: A combination tablet of tramadol and acetaminophen was effective and well tolerated for the treatment of FM related pain without any serious side effects.

Disclosure: The investigators at the 27 participating sites were financially reimbursed by Ortho-McNeill Pharmaceutical, Inc. for conducting this study.

Keywords: Fibromyalgia; Tramadol/Acetaminophen (APAP); efficacy and safety

NOTE: Warnings about seizure risk associated with Tramadol (Ultram) are posted on the FDA web site:

Tramadol HCL Tablets 50 Mg Scored

Proposed Package Insert


Seizure Risk

Seizures have been reported in patients receiving ULTRAM

within the recommended dosage range. Spontaneous post-

marketing reports indicate that seizure risk is increased with

doses of ULTRAM above the recommended range. Concomitant

use of ULTRAM increases the seizure risk in patients taking:

* Selective serotonin reuptake inhibitors (SSRI antidepressants or anorectics),

* Tricyclic antidepressants (TCAs), and other tricyclic

compounds (e.g., cyclobenzaprine, promethazine, etc.), or Opioids.

Administration of ULTRAM may enhance the seizure risk in

patients taking:

* MAO inhibitors (see also WARNINGS – Use with MAO Inhibitors),

* Neuroleptics, or

* Other drugs that reduce the seizure threshold.

Risk of convulsions may also increase in patients with epilepsy,those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In ULTRAM overdose, naloxone administration may increase the risk of seizure.

Anaphylactoid Reactions

Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with ULTRAM. These reactions often occur following the first dose. Other reported reactions include pruritus, hives, bronchospasm, and angioedema. Patients with a history of

anaphylactoid reactions to codeine and other opioids may be at

Source: FDA web site (www.fda.gov)

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