Pregabalin

Pregabalin

PEP Topic 
Chronic Pain
Description 

Pregabalin is an anticonvulsant used to relieve neuropathic pain and is used with other medications to treat certain types of seizures. It works by decreasing the number of pain signals that are sent out by damaged nerves in the body. Pregabalin comes as a capsule to be taken by mouth. Pregabalin has been studied in patients with cancer as an intervention for pain, peripheral neuropathy, and skin reactions. It has also been studied for its effect on anxiety and sleep-wake disturbances.

Effectiveness Not Established

Research Evidence Summaries

Garassino, M.C., Piva, S., La Verde, N., Spagnoletti, I., Iorno, V., Carbone, C., . . . Farina, G. (2013). Randomised phase II trial (NCT00637975) evaluating activity and toxicity of two different escalating strategies for pregabalin and oxycodone combination therapy for neuropathic pain in cancer patients. PloS One, 8(4), e59981.

doi: 10.1371/journal.pone.0059981
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Study Purpose:

To evaluate two different dose escalation approaches for the combination of oxycodone and pregabalin

Intervention Characteristics/Basic Study Process:

Patients were randomized to receive either 20 mg per day sustained-release oxycodone and escalating doses of pregabalin starting at 50 mg per day, or to pregabalin at 50 mg per day and escalating doses of oxycodone. Patients were observed for 14 days. The primary endpoint of the study was overall analgesia, defined as pain intensity reduction by at least one-third on a numeric rating scale.

Sample Characteristics:

  • N = 67
  • MEAN AGE = 67.5 years
  • AGE RANGE = 39–85 years
  • MALES: 56.7%, FEMALES: 43.3%
  • KEY DISEASE CHARACTERISTICS: Lung, breast, and colon cancer were most prevalent.
  • OTHER KEY SAMPLE CHARACTERISTICS: 72% had baseline pain scores of 6 or lower.

Setting:

  • SITE: Multi-site 
  • SETTING TYPE: Outpatient 
  • LOCATION: Italy

Phase of Care and Clinical Applications:

  • APPLICATIONS: Palliative care

Study Design:

  • Randomized, parallel group

Measurement Instruments/Methods:

  • Pain numeric rating scale
  • Allodynia recorded as present or absent by physical exam
  • Patient diary for daily recording of pain severity, use of other medications, and episodes of breakthrough pain

Results:

Analgesia as defined was achieved in the pregabalin escalation group with a mean dose of 100 mg and in the other group with a mean dose of 60 mg oxycodone. No differences were seen between groups in use of rescue medication, other analgesics, or side effects.

Conclusions:

Strategies for managing neuropathic pain with either dose escalation of pregabalin or escalation of sustained-release oxycodone when given in combination produced similar results.

Limitations:

  • Small sample (less than 100)
  • Risk of bias (no blinding)
  • Other limitations/explanation: Short duration of the study

Nursing Implications:

Findings suggest that similar pain management effects can be achieved with either escalation of pregabalin or escalation of oxycodone when given in combination for neuropathic pain. These findings suggest that either approach may provide similar effects and that the approach used can be determined according to relevant patient characteristics and preferences.

Mañas, A., Ciria, J.P., Fernández, M.C., Gonzálvez, M.L., Morillo, V., Pérez, M., . . . López-Gómez, V. (2011). Post hoc analysis of pregabalin vs. non-pregabalin treatment in patients with cancer-related neuropathic pain: Better pain relief, sleep and physical health. Clinical and Translational Oncology, 13, 656–663.

doi: 10.1007/s12094-011-0711-0
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Study Purpose:

To assess whether the use of pregabalin in combined therapy provides better health outcomes in patients with cancer-related neuropathic pain

Intervention Characteristics/Basic Study Process:

This study was a post hoc analysis of data from a previous epidemiologic study of clinical prevalence and analgesic management of neuropathic pain. Patients who received pregabalin versus those who did not were compared. Analgesic management was done at the individual physician’s discretion. Patients had a baseline visit and a final visit at eight weeks. In the initial study, patients were not randomized to different treatment, and numerous other interventions for analgesia were done.

Sample Characteristics:

  • The study reported on a sample of 273 patients.
  • Mean patient age was 62 years.
  • The sample was 55.6% male and 44.4% female.
  • Breast, lung, and genitourinary cancers were most prevalent.
  • All patients were receiving radiation therapy.

Setting:

  • Multisite
  • Outpatient setting
  • Spain

Phase of Care and Clinical Applications:

Patients were undergoing active antitumor treatment.

Study Design:

The study was a post hoc analysis of data from a previous epidemiologic study.

Measurement Instruments/Methods:

  • Brief Pain Inventory
  • Hospital Anxiety and Depression Scale
  • Medical Outcomes Sleep Scale
  • Short-Form Health Survey (SF-12)

Results:

The most frequent cause of neuropathic pain was the tumor itself, and cisplatin was the most frequently used chemotherapeutic agent. Fentanyl patches were used more frequently in the pregabalin group. Pain intensity improved in all patients at eight weeks, but improved more with pregabalin (change = 0, 9 points, p = 0.0084). Depression and anxiety decreased significantly in both groups. Physical component and mental component scores on the SF-12 improved in all patients, but improved more in those on pregabalin. When data were adjusted for age and sex, differences from baseline scores were less than 1. There were significant differences in groups in other medications used, numbers of analgesic interventions, and amount of radiation therapy treatment.

Conclusions:

It is difficult to draw any firm conclusions regarding efficacy of pregabalin from this study due to the differences in multiple other variables between study groups that could also affect the outcome measures used here. Changes from baseline measures seen at eight weeks were significant, but very small, raising the question of the clinical significance of results.

Limitations:

  • The study had baseline sample/group differences of import.
  • The study had risk of bias due to no control group, no blinding, no random assignment, and sample characteristics.
  • There were substantial differences in treatments used, as well as disease factors between groups compared here.

Nursing Implications:

No firm conclusions can be drawn from these results due to study limitations. Findings aim to show that use of pregabalin for neuropathic pain improves symptoms and  health outcomes. Differences from baseline reported here were small, suggesting lack of meaningful differences from a clinical perspective. Results point to the need for nurses to recognize the difference between statistical and clinical significance in evaluating intervention effects.

Mercadante, S., Porzio, G., Aielli, F., Ferrera, P., Codipietro, L., Lo Presti, C., & Casuccio, A. (2013). The effects of low doses of pregabalin on morphine analgesia in advanced cancer patients. The Clinical Journal of Pain, 29, 15–19.

doi: 10.1097/AJP.0b013e318247809a
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Study Purpose:

To evaluate the effectiveness of pregabalin as a coanalgesic on pain in patients with cancer-related pain

Intervention Characteristics/Basic Study Process:

Patients were assigned randomly to receive either sustained-release morphine or sustained-release morphine and pregabalin in increasing doses up to 150 mg per day. Oral morphine in doses of about one-sixth of the baseline dose was used for breakthrough pain. Other drugs were allowed, and patients already receiving non-opioid analgesics of steroids, antidepressants, or anticonvulsants could continue use.

Sample Characteristics:

  • N = 44
  • MEAN AGE = 65.5 years (SD = 10.3 years)
  • MALES: 55%, FEMALES: 45%
  • KEY DISEASE CHARACTERISTICS: Not reported

Setting:

  • SITE: Multi-site
  • SETTING TYPE: Outpatient
  • LOCATION: Italy

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Late effects and survivorship

Study Design:

  • RCT

Measurement Instruments/Methods:

  • Brief Pain Inventory
  • Pain intensity numeric rating scale
  • Symptoms assessed on a 1–3 scale

Results:

No significant differences were seen between groups in pain intensity or symptoms. Pain declined overall in both study groups. In both groups, opioid dosage used over time significantly increased.

Conclusions:

Findings did support improvement in chronic, uncontrolled pain with the use of pregabalin as a coanalgesic. Sample size was insufficient to analyze differences in neuropathic pain specifically.

Limitations:

  • Small sample (less than 100)
  • Risk of bias (no blinding)
  • Subject withdrawals 10% or more

 

Nursing Implications:

Findings did not show a benefit of adding pregabalin to strong opioids for improved management of uncontrolled cancer-related pain; however, the study had a small sample size because of loss of patients to follow-up–a typical challenge for studies in patients with advanced disease. Further research is needed into the appropriate role, dosage, and effective use of drugs such as pregabalin as coanalgesics.

Raptis, E., Vadalouca, A., Stavropoulou, E., Argyra, E., Melemeni, A., & Siafaka, I. (2014). Pregabalin vs. opioids for the treatment of neuropathic cancer pain: A prospective, head-to-head, randomized, open-label study. Pain Practice, 14, 32–42.

doi: 10.1111/papr.12045
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Study Purpose:

To determine the efficacy and safety of increasing opioid doses versus increasing doses of an adjuvant for patients with definite neuropathic cancer pain (i.e., neuropathic pain that occurred as a result of the disease, the treatment, or both). The goal was to achieve a 30% or more decrease in the visual analog scale (VAS) score compared to baseline.

Intervention Characteristics/Basic Study Process:

One hundred and twenty patients were divided via simple randomization into two groups. Baseline data were collected on all 120 patients (i.e., VAS score, meds, and full assessment). The first group was prescribed a starting dose of pregabalin at 75 mg per day and titrated up by 75 mg every third day as needed up to 600 mg per day divided into two doses, until adequate pain relief was achieved or adverse effects were noted. The second group was given 25 mcg per hour fentanyl patch and increased by 25 mcg per hour every 72 hours up to a max dose of 150 mcg per hour until adequate pain relief was achieved or adverse events were noted. Both groups had rescue oral morphine as needed.

Sample Characteristics:

  • N = 120  
  • AGE = Older than 18 years
  • MEAN AGE = Pregabalin group: 61.2 years (SD = 9.3 years); fentanyl group: 63.2 years (SD = 11.8 years)
  • MALES = 58, FEMALES = 62
  • KEY DISEASE CHARACTERISTICS: Diagnosed with definite neuropathic cancer pain
  • OTHER KEY SAMPLE CHARACTERISTICS: On second step of the World Health Organization analgesic ladder; resistant to a combination of codeine with paracetamol; a non-steroidal anti-inflammatory drug and methylprednisolone used for a minimum of three consecutive days; expected survival of two months or longer; normal renal function and a VAS score greater than 4 at baseline

Setting:

  • SITE: Single site   
  • SETTING TYPE: Not specified   
  • LOCATION: Athens, Greece

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Mutliple phases of care
  • APPLICATIONS: Elder care, palliative care

Study Design:

  • Prospective, head-to-head, comparative, randomized, open-label

Measurement Instruments/Methods:

  • Satisfaction Criterion (created by the authors for this study), which intended to define the level of pain relief considered appropriate for the study patients
  •  VAS

Results:

Changes in VAS scores showed no difference between groups, but the percentage change in these scores showed a significant reduction for the patients on pregabalin (-58% versus -50%). A greater percentage of patients on pregabalin achieved the study primary endpoint of at least a 30% reduction in pain VAS score (73.3% with pregabalin, 36.7% with fentanyl, p < .0001). No significant difference was seen in the proportion of patients needing rescue medication.

Conclusions:

For these patients with neuropathic pain, no significant differences were seen in efficacy of adjuvant pregabalin versus increasing opioid medication for pain control.

Limitations:

  • Authors created their own measurement tool.
  • Baseline VAS analysis was different between the two groups, with baseline  median pain lower in the opioid group—this could have made the defined reduction easier.
  • Short timeframe (four weeks)
  • The interventions compared involved two different routes of medication administration.
  • The dose limit on fentanyl (150 mcg per hour) was based on the groups’ pain center protocol, which dictates that patients on more than 150 mcg per hour fentanyl would need to be considered for a different treatment or intervention.
  • Limited information on any adverse events experienced by study participants
  • No information about the amount of rescue medication used in both groups, only the proportion of patients that used any rescue medication

Nursing Implications:

I find the results of this study to be useful for oncology professionals working with patients with neuropathic cancer pain, whether from the disease, the treatment, or both. A similar study using tramadol versus pregabalin for neuropathic cancer pain may be of value.

Guideline/Expert Opinion

National Comprehensive Cancer Network. (2011). NCCN Clinical Practice Guidelines in Oncology: Adult cancer pain [v. 2.2011]. Retrieved from http://www.nccn.org/professionals/physician_gls/pdf/pain.pdf

http://www.nccn.org/professionals/physician_gls/pdf/pain.pdf
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Type of Resource/Evidence-Based Process:

These guidelines do not provide any information about search strategy or any specific evaluation of evidence. Notes state that most direct evidence is of low quality, but recommendations do result from unanimous consensus.

Guidelines & Recommendations:

The guidelines provide detailed recommendations regarding:

  • Screening and assessment
  • Management of pain in opioid-naive as well as opioid-tolerant patients
  • Ongoing care of adult patients with cancer and related pain management
  • Comprehensive pain assessment and use of pain ratings
  • Interventions for specific types of pain syndromes
  • Opioid prescribing, titration, and ongoing management
  • Management of adverse effects related to opioids
  • Psychosocial support and patient and family education
  • Nonpharmacologic interventions.

Limitations:

In general, opioids are first-line interventions. The NCCN guidelines suggest that antidepressants and anticonvulsants can be first-line treatments for adjuvant pain, although the recommendation for using them as such is still based on anecdotal experience or guidelines relating to patients who do not have cancer.

Nursing Implications:

The NCCN guidelines provide comprehensive algorithms for pain management, from screening to ongoing maintenance. The guidelines recommend considering a variety of nonpharmacologic interventions. Psychosocial support, including coping-skills training, is recommended, as is comprehensive patient and family education. The guidelines provide useful information and an overview of the full range of pain management. The work points to the ongoing need to consider multiple adjuvant and supportive interventions to achieve pain relief that works for the individual patient.

Yamaguchi, T., Shima, Y., Morita, T., Hosoya, M., Matoba, M., & Japanese Society of Palliative Medicine. (2013). Clinical guideline for pharmacological management of cancer pain: The Japanese Society of Palliative Medicine recommendations. Japanese Journal of Clinical Oncology, 43, 896–909.

doi: 10.1093/jjco/hyt099
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Purpose & Patient Population:

PURPOSE: To summarize the recommendations and rationale for the pharmacologic management of cancer pain and identify the best practices in cancer pain management

TYPES OF PATIENTS ADDRESSED: Patients with cancer pain

Type of Resource/Evidence-Based Process:

RESOURCE TYPE: Consensus-based guideline  

PROCESS OF DEVELOPMENT: Task force established with 56 physicians, 25 pharmacists, 23 nurses, one epidemiologist, and seven other professionals; conducted systematic review; drafted recommendations using Delphi methods; developed recommendations based on GRADE system

DATABASES USED: PubMed, PaPaS, Cochrane, review of references in relevant guidelines, textbook review, review of JPSM and Palliative Medicine from January 2000–July 2008  

INCLUSION CRITERIA: Studies that evaluated drugs available in Japan

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Multiple phases of care 
  • APPLICATIONS: Pediatrics, elder care, palliative care 

Results Provided in the Reference:

Sixty-five recommendations were created—24 for general cancer pain management, 24 for managing specific etiologic pain syndromes, 15 for managing opioid-induced adverse effects, and 2 for patient education.

Guidelines & Recommendations:

Management of cancer pain includes assessment and an individualized approach to treating mild, moderate-to-severe, severe, and breakthrough pain. Opioids are the mainstay of treatment. Immediate-release (IR) or parenteral opioids should be used for unstable pain, whereas extended-release (ER) and IR opioids can be used for stable pain. Neuropathic pain should be managed with adjuvants (e.g., anticonvulsants, antidepressants, antiarrhythmics, ketamines, corticosteroids), metastatic bone pain with bisphosphonates, epigastric pain with celiac plexus block (pancreatic cancer), thoracic pain with nerve blocks, perineal pain with saddle block or superior hypogastric plexus block, malignant psoas syndrome with muscle relaxants or nerve block, and malignant bowel obstruction with octreotide, scopolamine, or corticosteroids. Adverse events of opioids should be judiciously treated: 1) nausea and vomiting with anti-dopaminergics, prokinetics, and antihistamines; opioid rotation, change of route, 2) constipation with laxatives; consider rotation to fentanyl, 3) drowsiness with psycho-stimulants; opioid rotation, route rotation. Patient education should be employed for all patients.

Limitations:

Only medications available in Japan are included. The focus is on pharmacologic interventions, but some psycho-educational aspects are included.

Nursing Implications:

Patient education is an important part of pain management. In addition, nurses can recommend pharmacologic and procedural strategies to help manage pain in specific patient populations.


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