Lumbar Stenosis Outcomes Research (LUSTOR) (LUSTOR)

Lumbar Stenosis Outcomes Research (LUSTOR)- A Randomized, Double-blind, Cross-over Trial of Pregabalin vs. Diphenhydramine in Patients With Lumbar Spinal Stenosis and Neuropathic Low Back Pain

The primary objective of the proposed pilot study is to determine the efficacy of pregabalin in prolonging the time to onset of pain and reducing the severity of pain associated with walking in patients with neurogenic claudication. Neurogenic claudication is defined as movement induced leg pain, numbness, heaviness, or vague discomfort in part or all of one or both legs provoked with walking and standing and relieved by sitting, squatting, or forward flexion posturing. The secondary objective is to examine the functional benefit of pregabalin with respect to improvement in duration and distance of walking.

Study Overview

• Status: Completed
• Conditions: Lumbar Spinal Stenosis
• Intervention / Treatment: Drug: Pregabalin; Drug: Diphenhydramine

Detailed Description

Subjects were randomized into one of two treatment sequences: pregabalin/active placebo or active placebo/pregabalin. Each arm lasted 10 days, with a washout period of 10 days between treatments. Pregabalin was administered as a standardized two step titration, starting at 75mg twice daily up to a maximum daily dose of 150mg twice daily; and likewise, diphenhydramine (active placebo) was administered starting at 6.25mg twice daily up to a maximum daily dose of 12.5mg twice daily. The primary endpoint was time to first symptoms of moderate intensity (NRS ≥ 4/10) during treadmill ambulation. Ambulation assessment was performed during the screening visit, and on day 10 of each period to evaluate pain intensity associated with walking as well as distance covered by the patients. Quantitative assessment of ambulation was conducted on a treadmill at 0° ramp incline at 1.2 miles per hour (mph). Measurement of self-reported symptom severity using the NRS at baseline, and every 30 seconds for a maximum of 15 minutes was recorded. The following information was also recorded: time to first symptoms, total ambulation time. The examination was stopped after 15 minutes or at the onset of severe symptoms. Severe symptoms were defined as the level of discomfort that would make patients stop walking in usual life situations. No one was encouraged or prompted to continue walking beyond this point. Patients were instructed to walk with an upright posture. They were not permitted to lean forward or hold onto the handrails during the examination. Secondary outcome measures included area under the curve of present pain intensity with ambulation at each specified time point, final pain intensity with walking, walking tolerance, time to return to baseline pain level after ambulation, as well as the results of a series of pain related questionnaires including: Visual Analog Scale (VAS), Patient Global Assessment (PGA), NRS, Roland Morris Disability Questionnaire (RMDQ), modified Brief Pain Inventory short form (mBPI-sf), Oswestry Disability Index (ODI), and Swiss Spinal Stenosis (SSS).

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • New York
    • Rochester, New York, United States, 14618
      • 2180 South Clinton Avenue

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must present with clinical symptoms of neurogenic claudication (neurogenic claudication is defined as movement induced leg pain, numbness, heaviness, or vague discomfort in part or all of one or both legs provoked with walking and standing and relieved by sitting, squatting, or forward flexion posturing) and endorse limitation of walking tolerance due to these symptoms
• Numeric Rating Scale (NRS) for pain greater than or equal to 6 in response to the following questions: "Circle one number (from 0=no pain to 10=worst pain)-How would you rate the worst leg and lower back pain you experienced during walking last week?"
• Patients must have confirmatory imaging by MRI or CT scan demonstrating at least one level of lumbar spinal stenosis within 1 year
• Duration of symptoms > 3 months
• Age > 50 years; male or female

Exclusion Criteria:

• Past or present existence of movement disorder, e.g., Parkinsonism,or a neurologic disease that might affect the ability to ambulate (e.g., signs/symptoms of cauda equina compression)
• Cognitive impairment preventing full understanding or participation in the study
• Peripheral vascular disease
• Moderate to severe arthritis of the knee or hip that might severely compromise ambulation
• Past or present lower extremity peripheral vascular disease
• Serious concomitant medical illness (e.g., heart disease) that might impair ambulation assessment
• Previous lumbar surgery for spinal stenosis (laminectomy with or without fusion) within the past 2 years
• Prior treatment with study drug for neurogenic claudication
• Severe psychiatric disorder
• Mean time to severe symptoms > 15 minutes.
• Epidural steroid treatment within the last three months
• Ongoing treatment with gabapentin
• Hypersensitivity or allergic reaction to diphenhydramine

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Pregabalin then Diphenhydramine; Pregabalin started at 75mg twice daily for 3 days; pregabalin increased to 150mg twice daily for 7 days; pregabalin reduced to 75mg twice daily for 3 days; no drug for 7 days; diphenhydramine started at 6.25mg twice daily for 3 days; diphenhydramine increased to 12.5mg twice daily for 7 days; diphenhydramine reduced to 6.25mg twice daily for 3 days.	Drug: Pregabalin; Pregabalin started at 75mg twice daily for 3 days; pregabalin increased to 150mg twice daily for 7 days; pregabalin reduced to 75mg twice daily for 3 days.; Other Names: Lyrica; Drug: Diphenhydramine; diphenhydramine started at 6.25mg twice daily for 3 days; diphenhydramine increased to 12.5mg twice daily for 7 days; diphenhydramine reduced to 6.25mg twice daily for 3 days.; Other Names: Benedryl
Other: Diphenhydramine then Pregabalin; diphenhydramine started at 6.25mg twice daily for 3 days; diphenhydramine increased to 12.5mg twice daily for 7 days; diphenhydramine reduced to 6.25mg twice daily for 3 days; no drug for 7 days; pregabalin started at 75mg twice daily for 3 days; pregabalin increased to 150mg twice daily for 7 days; pregabalin reduced to 75mg twice daily for 3 days.	Drug: Pregabalin; Pregabalin started at 75mg twice daily for 3 days; pregabalin increased to 150mg twice daily for 7 days; pregabalin reduced to 75mg twice daily for 3 days.; Other Names: Lyrica; Drug: Diphenhydramine; diphenhydramine started at 6.25mg twice daily for 3 days; diphenhydramine increased to 12.5mg twice daily for 7 days; diphenhydramine reduced to 6.25mg twice daily for 3 days.; Other Names: Benedryl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to First Symptoms of Moderate Pain	Using the Numeric Rating Scale (NRS) (0=no pain, 10=worst pain imaginable)the time to first symptoms (Tfirst) with a NRS score greater than or equal to 4 (moderate pain level), with treadmill ambulation was measured.	10 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Final Pain as Measured by NRS	Subjects were instructed to walk on the treadmill and to tell the research coordinator to stop testing when they reached the point at which they typically would need to stop and sit down, or until 15 minutes had elapsed. At defined intervals subjects were asked what their pain level was according to the NRS. When the subject reached their maximum distance, they were asked their NRS score. This was recorded as final pain intensity. Using the Numeric Rating Scale (NRS) (0=no pain, 10=worst pain imaginable)the time to first symptoms (Tfirst) with a NRS score greater than or equal to 4 (moderate pain level), with treadmill ambulation was measured.	10 days
Total Distance	Subjects were instructed to walk on the treadmill and to tell the research coordinator to stop testing when they reached the point at which they typically would need to stop and sit down, or until 15 minutes had elapsed. When the subject reached their maximum distance, the treadmill testing was stopped. This was recorded as total distance based on number of minutes and seconds walked. Minutes was converted to meters based on calculation of defined speed of the treadmill.	10 days
Recovery Time	After the subject completed the treadmill test they were asked to immediately return to the seated position. At this point a timer was started. When the subjects pain level returned to baseline (level of pain subject felt in a seated position before walking) the time was stopped. This was recorded as recovery time. Maximum recovery time is 15 minutes.	10 days
Area Under the Curve	Subjects were instructed to walk on the treadmill and to tell the research coordinator to stop testing when they reached the point at which they typically would need to stop and sit down, or until 15 minutes had elapsed. At defined intervals (every 30 seconds) subjects were asked what their pain level was according to the NRS. The area under the curve of present pain intensity multiplied by the amount of time the subject walked.	10 days
Visual Analog Scale (VAS)	The VAS asked subjects to place a mark indicative of their low back pain during the past day on a 100mm line, with 0mm representing no pain and 100mm representing extreme pain.	10 days
Oswestry Disability Index (ODI) Score	The ODI is a set of 10 questions each with five choices (maximum score of 5 points per question) designed to determine how back pain has affected the ability to manage everyday life (pain intensity, personal care, lifting, walking, sitting, standing, sleeping, social life, traveling, and change positions). A total score range of 0-50; score of 0 indicates no disability and a score of 50 would indicate 100% disability.	10 days
Swiss Spinal Stenosis (SSS) Score- Symptom Severity	The SSS is a series of questions asking about symptom severity, physical function, and satisfaction. The symptom severity section is a set of 7 questions (maximum score is 5 points per question) and asks to rate pain for each question based on no pain, mild, moderate, severe or very severe pain. The total score (maximum=35) is added up and divided by seven. The maximum score for the symptom severity section (score=5) indicates very severe symptom severity.	10 days
Swiss Spinal Stenosis- Physical Function	The SSS is a series of questions asking about symptom severity, physical function, and satisfaction. The physical function section is a series of 5 questions (maximum 4 points per question) and asks to rate function for each question based on comfortably, sometimes with pain, always with pain, no functional ability. The total score (max=20) is divided by five. The maximum score for the physical function section (max=4) indicates no ability to function.	10 days
Modified Brief Pain Inventory (mBPI)- Interference Score	The mBPI is a series of questions that rates the severity and impact of pain on daily function. The questionnaire is made up of 4 pain severity items using the NRS scale, and seven pain interference sub-scales. The final interference score is an average of the seven sub-scales (0 indicating no interference and 10 indicating complete interference).	10 days
Roland Morris Disability Questionnaire	The RMDQ consists of 24 yes/no statements about activity limitations due to back pain. These questions center on movement, ambulation, and self-care activities. Positive (yes) answers each contribute 1 point to cumulative score with total scores ranging from 0 (no disability) to 24 (severely disabled).	10 days
Patient Global Assessment (PGA)	Subjects were asked to rate their low back pain according to the PGA. PGA is the impact of disease activity. PGA was measured on a 5-point scale, where 1=very good, 2=good, 3=fair, 4=poor, and 5=very poor.	10 days

Collaborators and Investigators

• Sponsor: University of Rochester
• Collaborators: Pfizer
• Investigators: Principal Investigator: John D Markman, M.D, University of Rochester

Publications and helpful links

General Publications

• Stucki G, Daltroy L, Liang MH, Lipson SJ, Fossel AH, Katz JN. Measurement properties of a self-administered outcome measure in lumbar spinal stenosis. Spine (Phila Pa 1976). 1996 Apr 1;21(7):796-803. doi: 10.1097/00007632-199604010-00004.
• Simon LS, Evans C, Katz N, Bombardier C, West C, Robbins J, Copley-Merriman C, Markman J, Coombs JH. Preliminary development of a responder index for chronic low back pain. J Rheumatol. 2007 Jun;34(6):1386-91.
• Markman JD, Dworkin RH. Ion channel targets and treatment efficacy in neuropathic pain. J Pain. 2006 Jan;7(1 Suppl 1):S38-47. doi: 10.1016/j.jpain.2005.09.008.
• Deen HG Jr, Zimmerman RS, Lyons MK, McPhee MC, Verheijde JL, Lemens SM. Test-retest reproducibility of the exercise treadmill examination in lumbar spinal stenosis. Mayo Clin Proc. 2000 Oct;75(10):1002-7. doi: 10.4065/75.10.1002.
• Deen HG, Zimmerman RS, Lyons MK, McPhee MC, Verheijde JL, Lemens SM. Use of the exercise treadmill to measure baseline functional status and surgical outcome in patients with severe lumbar spinal stenosis. Spine (Phila Pa 1976). 1998 Jan 15;23(2):244-8. doi: 10.1097/00007632-199801150-00019.

Study record dates

Study Major Dates

• Study Start: March 1, 2008
• Primary Completion (Actual): March 1, 2010
• Study Completion (Actual): September 1, 2010

Study Registration Dates

• First Submitted: March 12, 2008
• First Submitted That Met QC Criteria: March 12, 2008
• First Posted (Estimate): March 19, 2008

Study Record Updates

• Last Update Posted (Estimate): June 20, 2016
• Last Update Submitted That Met QC Criteria: May 11, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: Neurogenic claudication, lumbar spinal stenosis, treadmill testing
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Pathological Conditions, Anatomical; Spinal Diseases; Bone Diseases; Constriction, Pathologic; Spinal Stenosis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics; Antiemetics; Gastrointestinal Agents; Dermatologic Agents; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; Hypnotics and Sedatives; Anti-Anxiety Agents; Anticonvulsants; Anesthetics, Local; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Anti-Allergic Agents; Sleep Aids, Pharmaceutical; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Antipruritics; Diphenhydramine; Promethazine; Pregabalin
• Other Study ID Numbers: 16697; IIR#GA00818X (Other Identifier: Sponsor ID)