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Evidence Table 7

Randomized-controlled trials in patients with chronic pain

Author
Year
Country
Trial Name
(Quality Score)
Study Design SettingEligibility criteriaInterventionsRun-in/Washout PeriodAllowed other medications/ interventionsMethod of Outcome Assessment and Timing of AssessmentAge Gender EthnicityOther population characteristicsNumber screened/ eligible/ enrolledNumber withdrawn/ lost to fu/analyzedResultsMethod of adverse effects assessmentAdverse eventsTotal withdrawals; withdrawals due to adverse eventsComments
Kimos, 2007
Canada
DB RCT, multicenterFemales 18–45y were recruited; diagnosis of masticatory muscle pain based on the diagnostic classification of Dworkin and LeResche for at least 6m that is not attributable to recent acute trauma or previous infection or active inflammatory cause; moderate to severe baseline score of > 50mm using a 100m VAS; pain upon palpation in > 3 points (anterior, medial and posterior temporalis; or deep, inferior ro anterior portion of the masseter); patients seeking treatment for TMD/Orofacial pain clinic considered for participation as well

Patients were excluded if there was clinical evidence of inflammatory TMD; were pregnant or nursing; had epilepsy, cardiac, renal or hepatic disorders; were intolerant to gabapentin; had dental or periodontal disease, oral pathology lesions, oral infection or neuropathic facial pain; any patients wearing occlusal splint appliance < 6m
Gabapentin 300 mg/d, increased 300 mg every 3d, maximum dose 4200 mg; if medication discontinued for any reason, a decrease of 300 mg every 3d occurred; study medication for 12wIn cases where patient required analgesic medication, patients reported on second visit after 1w washout periodSubjects asked to discontinue any pain medications (relaxants, anti- inflammatories, or combination drugs - e.g. narcotics and acetaminophen) and other medications that could influence pain (e.g., hypnotics)

Other drugs allowed (TCA, benzodiazepines, specific serotonin re-uptake inhibitors) as long as there were no changes to dosage regimen

Acetaminophen 500 mg used for breakthrough pain; instructed to take it every 6 h with maximum of 4000 mg/d

Gabapentin vs. placebo TCAs: 0(0%) vs. 2(10%) SSRIs: 8(33%) vs. 5(25%)
CMM pain intensity and daily function measured on a 10cm VAS; the number of tender sites using the palpation index (positive and negative responses)Age: 33.58
Male: 0(0%)
Ethnicity: NR
Gabapentin vs placebo Tension headache: 14(56%) vs. 10(40%)
Poor sleep quality: 12(48%) vs. 5(20%)
Recurrent headaches: 11(44%) vs. 7(28%)
Neck pain: 4(16%) vs. 3(12%)
Migraines: 2(8%) vs. 4(16%)
Fibromyalgia: 1(4%) vs. 0(0%)
79 screened / 50 eligible / 50 enrolled / 50 randomized14 withdrawn / lost to follow-up not reported / 44 analyzedGabapentin vs. placebo

VAS-pain, reduction (%):51.04(38.89) vs. 24.30(43.54); between-group, p=0.037

Palpation index, reduction: 6.46(4.11) vs. 1.90(5.02); between-group, p=0.002

VAS-function, reduction (%):52.61(42.42) vs. 18.63(55.22); between-group, p=0.026
Method of AE assessment not reportedGabapentin vs. placebo
Dizziness: 7(28%) vs. 2(8%); p=0.69
Drowsiness: 7(28%) vs. 5(20%); p=0.37
Memory/cognitive impairment: 4(16%) vs. 1(4%); p=0.17
Dry mouth: 3(12%) vs. 1(4%); p=0.30
Fatigue: 3(12%) vs. 2(8%); p=0.50
Ataxia: 1(4%) vs. NR
Diarrhea: 1(4%) vs. 1(4%); p=0.75
Constipation: 1(4%) vs. NR
Weight gain: 1(4%) vs. NR
Chest tightness: 1(4%) vs. NR
Numbness: NR vs. 1(4%)
Accelerated HR: NR vs. 1(4%)
Gabapentin vs placebo
Total withdrawals: 6/25(24%) vs. 8/25(32%)
Withdrawals due to AEs: 4/50(8%)
ITT population: Gabapentin 24(48%) vs. placebo 20(40%); 6(12%) did not provide any follow-up visit

A number of patinets were not compliant in completing their escape medication calendar; a further analysis of use of escape medication not feasible

Positive correlation (r=0.70) in VAS-pain and palpation index

Gabapentin showed statistically significant decresed in VAS-pain score (p=0.026), palpation index (p<0.001) and VAS-function (p=0.013)

Main effects of time were significant in all three measures (p<0.001)

No statistically significant interactions between time and study groups for VAS- pain (p=0.425) and -function (p=0.076) except PI (p=0.004)

Number needed to treat to reduced pain in one: 4
Muehlbacher M, 2006
Austria
DB RCTPatients with chronic lower back pain > 6m with no neurological deficits; aged 18 or older.

Patients were excluded if they were in acute psychotic or manic episodes; using opioids or topiramate; had cancer, systemic or cardiopulmonary disease; acute suicidality; alcohol or drug abuse; pregnant
Topiramate 50 mg/d (titrated 50 mg/wk to dose of 300 mg/d or placebo for 10wNot reportedPatients asked to refrain from analgetic or anti-inflammatory drugs 1w before participation (novalgine, paracetamol, diclofenac, ketoprofen, ibuprofen)

Antidepressant medications allowed (mirtazapine, paroxetine, venlafaxine, fluoxetine, amitriptyline, maprotiline, and doxepine
Structured Clinical Interview; German versions of the MPQ, State-Trait Anger Expression Inventory (STAXI), Oswestry Low Back Pain Disability Questionnaire (OLBPQ) and the SF-36 Health Survey to measure pain, anger, QoL and HRQoLTopiramate vs. placebo
Age: 48.8(5.4) vs. 48.7(5.0)
Male: 29(60%) vs. 31(65%)
Ethnicity: Not reported
Topiramate vs. placebo
Weight (kg): 92.7(10.6) vs. 91.2(10.1)
Partnership: 31(65%) vs. 31(65%)

Depressive disorders: 13(27.1%) vs. 12(25.0%)
Anxiety disorders: 4(8.3%) vs. 3(6.25%)

Pain duration (y): 2.5 vs. 2.0

Leg pain: 6(12.5%) vs. 4(8.3%)
134 screened / 111 eligible / 111 enrolled / 96 randomized7 lost to follow-up / 96 analyzedTopiramate vs. placebo
Mean changes: State-anger: -2.4 vs. −0.4
Trait-anger: −2.6 vs. −0.4
Anger-in: −2.1 vs. 0.1
Anger-out: −3.7 vs. −0.1
Anger-control: 1.0 vs. 0.0
Body weight (kg): −6.5 vs. −0.2
Pain rating index: −12.9 vs. −1.5
Physical functioning: 8.7 vs. −0.4
Role-physical: 8.7 vs. 0.4
Bodily pain: 4.1 vs. 0.9
General health: 5.4 vs. 0.9
Vitality: 6.7 vs. 0.6
Social functioning: 4.1 vs. 0.6
Role-emotional: 1.2 vs. 0.6
Mental health: 4.8 vs. 0.5

Between-group, p<0.001 for all outcomes measured except role-emotional (p=0.096)
Side-effects measured using a nonstructured questionnaireTopiramate vs. placebo Somnolence: 2(4.2%) vs. 0(0%)
Vision problems: 2(4.2%) vs. 1(2.1%)
Psychomotor slowing: 2(4.2%) vs. 1(2.1%)
Memory problems: 2(4.2%) vs. 1(2.1%)
Dizziness: 5(10.4%) vs. 3(6.25%)
Headache: 4(8.3%) vs. 3(6.25%)
Paresthesia/tremor: 3(6.25%) vs. 1(2.1%)
Topiramate vs. placebo Total withdrawals: 2/48(4.2%) vs. 5/48(10.4%) Withdrawals due to AEs: Not reportedMale and female demographic data reported in table 1

Rapid changes occurred in the topiramate group between 3 and 5w of treatment (figures 25)
Todorov, 2005
U.S.
Open-label
Single-center, general neurology practice
Candidates for treatment with gabapentin: diagnosed with chronic pain (e.g., musculoskeletal headaches, failed back syndrome, posttraumatic cervical strain, fibromyalgia); stabilized on current medications and still symptomatic; not been previously treated with tiagabine or gabapentinTiagabine 4 mg/d (2 mg bid, when needed the dose increased by 4 mg until optimum response, maximum dose 24 mg/d, mean 15 mg/d) vs. Gabapentin 200 mg/d (100mg bid, increased by 300 mg every week until optimum respose, maximum dose 2400 mg/d, mean 915 mg/d) for 3mNot reportedPatients allowed to continue analgesic or antidepressant therapy that were stabilized prior to study entry

Tiagabine vs. Gabapetin
NSAIDs: 10(22%) vs. 8(17%)
Analgesics: 12(26%) vs. 11(24%)
Antidepressants: 17(37%) vs. 11(24%)
Anxiolytics: 7(15%) vs. 11(24%)
Hypnotics: 4(9%) vs. 1(2%)
Antimigrane: 6(20%) vs. 2(4%)
Muscle relaxants: 6(20%) vs. 1(2%)
Others: 25(54%) vs. 22(49%)
Patients rated pain intensity and sleep quality using 11- point scales, 0 (no pain) to 10 (excruciating pain) at baseline and 3mTiagabine vs. Gabapetin
Age: 46.0(13.7) vs. 42.0(12.0)
Male (%):12(26%) vs. 8(18%)
Ethnicity: Not reported
Tiagabine vs. Gabapentin
Musculoskeletal headache: 21(46%) vs. 23(51%)
Cervical pain: 12(26%) vs. 11(24%)
Neuropathic pain: 8(17%) vs. 2(4%)
Lumbar pain: 3(7%) vs. 5(11%)
Multiple pain syndrome: 2(4%) vs. 4(9%)

Pain intensity: 7.78(0.32) vs. 6.91(0.30)
Sleep quality: 6.88(0.44) vs. 6.96(0.33)
Number screened not reported/91 eligible/91 enrolled/91 randomized17 withdrawn/9 lost to follow-up/91 analyzedTiagabine vs. Gabapentin

Mean change, pain intensity: - 2.3 (p<0.001) vs. -1.2 (p=0.008); NSD between- groups

Mean change, sleep quality: - 3.0 (p=0.001) vs. -1.54 (p=0.019); between-group, p=0.04
AEs reported throughout studyGastric upset most common AEs in Tiagabine, lead to 4 withdrawals

Dizziness/drowsiness most common AEs in Gabapetin, lead to 4 withdrawals
Tiagabine vs. Gabapentin
Total withdrawal: 10/46(22%) vs. 7/45(16%)
Withdrawals due to AEs: 4/46(8.7%) vs. 4/45(11.1%)

From: Evidence Tables

Cover of Drug Class Review: Antiepileptic Drugs for Indications Other Than Epilepsy
Drug Class Review: Antiepileptic Drugs for Indications Other Than Epilepsy: Final Report Update 2 [Internet].
McDonagh M, Peterson K, Lee N, et al.
Portland (OR): Oregon Health & Science University; 2008 Oct.
Copyright © 2008, Oregon Health & Science University, Portland, Oregon.

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