Pregabalin for chronic prostatitis (Review) Aboumarzouk OM, Nelson RL The Cochrane Library

Transcription

Pregabalin for chronic prostatitis (Review)
Aboumarzouk OM, Nelson RL
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2012, Issue 8
http://www.thecochranelibrary.com
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . .
ABSTRACT . . . . . . . . .
PLAIN LANGUAGE SUMMARY .
BACKGROUND . . . . . . .
OBJECTIVES . . . . . . . .
METHODS . . . . . . . . .
RESULTS . . . . . . . . . .
Figure 1.
. . . . . . . .
Figure 2.
. . . . . . . .
Figure 3.
. . . . . . . .
DISCUSSION . . . . . . . .
AUTHORS’ CONCLUSIONS . .
ACKNOWLEDGEMENTS
. . .
REFERENCES . . . . . . . .
CHARACTERISTICS OF STUDIES
DATA AND ANALYSES . . . . .
HISTORY . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS
DECLARATIONS OF INTEREST .
SOURCES OF SUPPORT . . . .
INDEX TERMS
. . . . . . .
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
1
1
2
2
3
3
5
6
7
7
8
9
9
10
11
14
14
14
14
14
14
i
[Intervention Review]
Pregabalin for chronic prostatitis
Omar M Aboumarzouk1 , Richard L Nelson2
1 Dept.
of Urology, Wales Deanery, Cardiff, UK. 2 Department of General Surgery, Northern General Hospital, Sheffield, UK
Contact address: Omar M Aboumarzouk, Dept. of Urology, Wales Deanery, 40 Hollybush Road, Cyncoed, Cardiff, Wales, CF23 6TA,
UK. [email protected]. [email protected].
Editorial group: Cochrane Prostatic Diseases and Urologic Cancers Group.
Publication status and date: New, published in Issue 8, 2012.
Review content assessed as up-to-date: 29 May 2012.
Citation: Aboumarzouk OM, Nelson RL. Pregabalin for chronic prostatitis. Cochrane Database of Systematic Reviews 2012, Issue 8.
Art. No.: CD009063. DOI: 10.1002/14651858.CD009063.pub2.
ABSTRACT
Background
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a condition that is detrimental to the quality of life of men. Evidence
suggests that it may have a neuropathic origin and therefore medications such as pregabalin might have a role in the controlling of
symptoms.
Objectives
The primary objective was to compare pregabalin to other modalities of pain relief to alleviate men’s symptoms of CP/CPPS.
The secondary objective was to assess the safety and effectiveness of pregabalin to improve various individual symptoms consistent with
CP/CPPS.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1966 to May 2012), EMBASE (1980
to May 2012), CINAHL, clinicaltrials.gov, Google Scholar, and reference lists of articles and abstracts from conference proceedings,
without language restriction for pregabalin treatment of Class III prostatitis and CP/CPPS.
Selection criteria
Randomized controlled trials (RCTs) comparing pregabalin to placebo or other types of analgesics for the management of patients with
CP/CPPS were included. Patients with known causes of pain/discomfort were excluded.
Data collection and analysis
Only one RCT was included. The trial compared pregabalin to placebo for patients who had CP/CPPS.
Main results
For men who responded clinically (≥ 6-point improvement), there was no difference between the pregabalin (103/218; 47.2%) and
placebo (38/106; 35.8%) arms (risk ratio (RR) 1.32; 95% CI 0.99 to 1.76). There was less pain with a higher point improvement in
the pregabalin group compared to the placebo group (4.2 points versus 1.7 points, respectively; mean difference (MD) -2.3 points;
95% CI -4.0 to -0.7 points).
Though 59% (191/324) of the patients developed side effects, no serious effects were experienced. There were significantly more
neurologic side effects in the pregabalin group compared to the placebo group (38.5% (84/218) versus 22.6% (24/106), respectively;
1
RR 1.7; 95% CI 1.15 to 2.51), and less pain in the pregabalin group than in the placebo group (17.4% (38/218) versus 33.3% (35/106),
respectively; RR 0.53; 95% CI 0.36 to 0.78). However, no significant differences were seen between the pregabalin and placebo groups
with regards to gastrointestinal disturbances (18.3% (40/218) versus 18.9% (20/106), respectively; RR 0.97; 95% CI 0.60 to 1.58),
ocular/visual symptoms (6.9% (15/218) versus 2.8% (3/106), respectively; RR 2.43; 95% CI 0.72 to 8.22), and renal/genitourinary
symptoms (5.5% (12/218) versus 1.9% (2/106), respectively; RR 3.03; 95% CI 0.67 to 13.79).
Authors’ conclusions
There is evidence from one RCT that pregabalin does not improve CP/CPPS symptoms and causes adverse effects in a large percentage
of men. However, research is required to assess further whether pregabalin has a role in patients with CP/CPPS for symptom control.
PLAIN LANGUAGE SUMMARY
The use of pregabalin analgesia for patients with chronic prostatitis/chronic pelvic pain syndrome
It has been suggested that chronic prostatitis/chronic pelvic pain syndrome is due to pain caused by the nerves in or around the prostate.
Pregabalin is a pain killer that is specific for nerve pain. Therefore we conducted a search of the literature to evaluate the use of pregabalin
for this ailment and whether or not it was better than placebo.
We concluded that pregabalin was no more effective than placebo and is associated with adverse effects.
Though there was no conclusive evidence for the use of pregabalin, further research is recommended.
BACKGROUND
Description of the condition
Prostatitis has been generally defined as inflammation of the
prostate; however, this is a misnomer as not all patients with this
condition have prostatic inflammation (Weiss 2001). Fifty per cent
of men will experience one form of prostatitis during their life
(Bartoletti 2007; Weiss 2001), while 3% will have pelvic pain, and
10% painful ejaculation (Bartoletti 2007). Through the National
Institutes of Health (NIH) the International Prostatitis Collaborative Network (NIH-IPCN) has classified this clinical entity and
redefined it (Bartoletti 2007; Krieger 1999).
1. Class I: acute bacterial prostatitis;
2. Class II: chronic bacterial prostatitis;
3. Class III: chronic prostatitis/chronic pelvic pain syndrome
(CP/CPPS):
i) Class IIIA: inflammatory;
ii) Class IIIB: non inflammatory;
4. Class IV: asymptomatic inflammatory prostatitis.
Class I, as its description implies, is caused by an acute bacterial infection, while chronic bacterial prostatitis (Class II) is due
to recurrent episodes of bacterial urinary tract infections (UTIs)
(Krieger 1999; Reynard 2006; Weiss 2001). Class IV patients are
those who have no symptoms, but during prostate biopsy investi-
gation prostatic inflammation was found (Krieger 1999). Ten per
cent of patients fit into these three classifications (Classes I, II, IV),
with the remaining 90% being Classes IIIA or IIIB (Collins 1998;
Krieger 1999; Weiss 2001).
The incidence of CP/CPPS is about 3.3/1000 persons per year,
with a prevalence of 9% to 16% in the general male population,
and with an annual cost in 2001 of USD4397 per person (Collins
1998; CPCRN 2004; Nickel 2001; Pontari 2007; Roberts 1998).
CP/CPPS is detrimental to the quality of life of patients and accounts for 8% of visits to a urologist and 1% of visits to a general
practitioner in the US (Bartoletti 2007; Johansen 2002; Strauss
2010).
To be diagnosed with CP/CPPS, patients must have one or more of
the following symptoms over a three-month period (Litwin 1999;
Magri 2010; McNaughton Collins 2008; Reynard 2006):
• localized pain to the perineum, supra pubis, penis, or groin;
• pain during ejaculation;
• lower urinary tract symptoms (LUTS), such as dysuria
(painful urination), frequency, nocturia (night-time urination),
urgency, and poor stream flow;
• sexual and psychosocial disturbances.
These symptoms lead to the formation of a symptom index by
which the severity can be scored, where 0 to 9 is mild, 10 to 18 is
moderate, and 19 to 31 is severe (’Online Symptom Index’).
2
Though CP/CPPS is a common condition, little is known about
the pathophysiology and etiology. However, numerous hypotheses
do exist for both Class III sub classifications (IIIA and IIIB). For
example, with Class IIIA the theory is that inflammation is caused
by micro-organisms (Weiss 2001) whereas for Class IIIB, it is theorized that urine refluxes (flows backward) into the prostatic ducts
leading to inflammation, either due to bladder neck spasms, pelvic
floor muscle spasms, or increased tone (Weiss 2001). Moreover,
there are other suggestions that perineal microtrauma might be a
cause, owing to higher prostate-specific antigen (PSA) in sportsmen, and especially cyclists (Bartoletti 2007). However, the etiology of both classifications remains to be confirmed (CPCRN
2004; Strauss 2010).
Though there have not been any recent breakthroughs in understanding the pathophysiology or etiology of CP/CPPS, one study
has shown that some lifestyle and dietary factors were significantly higher in patients with CP/CPPS than in healthy individuals (Bartoletti 2007). CP/CPPS was found to be more prevalent in
patients who smoke, practice coitus interruptus, have sexual relationships with more than one partner, and consume a high caloric
diet - specifically milk, cheese, pasta, rice and cake, with low fruit
and vegetable consumption.
Description of the intervention
Pregabalin, approved by the European Agency for the Evaluation
of Medicinal Products (EAEMP) and the US Food and Drug
Administration (FDA), is an antiepileptic drug that is also effective for neuropathic pain control (Arnold 2010; Cappuzzo 2009;
Dworkin 2010; Jain 2005). Pregabalin is a derivative of the inhibitory neurotransmitter gamma aminobutyric acid (GABA) but
does not bind to GABA (Arnold 2010; Cappuzzo 2009; Jain
2005). It selectively binds to alpha2-delta protein subunits of voltage-gated calcium channels in the brain and the superficial dorsal horn of the spinal cord, thus reducing the influx of calcium
into synaptic endings. This in turn inhibits the release of excitatory neurotransmitters that stimulate neurons (Dworkin 2005;
Jain 2005).
Pregabalin is well absorbed, has an oral bioavailability of >
90%, and is excreted by the kidneys with minimal metabolism
(Cappuzzo 2009). Its main side effects include dizziness, somnolence, and peripheral edema, although there are also reports of
dry mouth, blurred vision, weight gain, ataxia (lack of co-ordinated muscle movement), headache, and nausea (Arnold 2010;
Cappuzzo 2009). However, in spite of these, pregabalin has been
shown to be effective and well tolerated for the management of
neuropathic pain (Arnold 2010).
Owing to the highly detrimental impact of CP/CPPS on the quality of life of men, there have been numerous studies, including RCTs and cohort studies, conducted to find a satisfactory
method of alleviating symptoms (Gottsch 2010; Johansen 2002;
McNaughton Collins 2008; Reynard 2006; Sikiru 2008; Strauss
2010; Weiss 2001).
Some studies have found evidence to suggest that CP/CPPS is
neuropathic (i.e. pathology of the peripheral nerves) in nature.
Pontari found that men with CP/CPPS were five times more likely
to have neurologic diseases, such as migraine headaches, vertebral
disk disease, or numbness or tingling in their limbs, than men who
did not have CP/CPPS (Pontari 2005). In addition, studies have
found abnormalities in the autonomic nervous system in patients
with CP/CPPS, causing pain sensitization (becoming highly sensitive) (Yang 2003; Yilmaz 2007). Furthermore, nerve-growth factor, a neurotrophin that acts as a mediator in neurogenic inflammation, has been found to have a role in CP/CPPS (Miller 2002).
Therefore, a neuropathic analgesic, such as pregabalin, might have
a role in alleviating symptoms in patients with CP/CPPS.
Why it is important to do this review
A thorough review of the literature and a meta-analysis or review
of the data is required to evaluate whether or not pregabalin is an
effective modality to control the symptoms of CP/CPPS. Furthermore, a review of the safety of pregabalin is also necessary to weigh
against its benefits.
OBJECTIVES
The primary objective was to assess the overall effectiveness of
pregabalin compared to other types of pain relief and to improve
overall symptoms of CP/CPPS.
The secondary objective was to assess the effectiveness of pregabalin to improve LUTS, pain/discomfort, and overall quality of
life, in addition to assessing side effects from the drug.
METHODS
Criteria for considering studies for this review
Types of studies
How the intervention might work
Randomized controlled trials (RCTs) comparing pregabalin to
placebo or any other analgesic for CP/CPPS were considered for
inclusion.
3
Types of participants
Participants were patients who had CP/CPPS Classes IIIA or IIIB.
Patients who had chronic pain due to a known cause were excluded
(e.g. infection, catheter in situ, previous surgery or radiation therapy, cancer).
Types of interventions
Patients receiving pregabalin were compared to those receiving a
placebo, an analgesia, or any other method of symptom relief.
11. World Health Organization (WHO) International Clinical
Trials Registry Platform (www.who.int/ictrp/en/);
12. www.clinicalstudyresults.org/.
The following search strategy was used to identify relevant RCTs:
1. Prostatitis OR Chronic Prostatitis OR Chronic Pelvic Pain
Syndrome,
2. Pregabalin,
3. Randomized Control Trials,
4. Men,
5. #1 AND #2,
6. #1 AND #2 AND #3,
7. #1 AND #2 AND #3 AND #4.
Types of outcome measures
Searching other resources
Primary outcomes
• Improvement in men’s overall symptoms: judged clinically
(an improvement of 6 or more points), measured by the NIHChronic Prostatitis Symptom Index (NIH-CPSI) score, where
the range of pain or discomfort = 0 to 21, urinary symptoms = 0
to 10, and quality of life impact = 0 to 12, with a total range of 0
to 43 (Online Symptom Index). A higher score indicates worse
discomfort, symptoms, and quality of life. The levels used, based
on the final score, are grouped into mild (0 to 9), moderate (10
to 18), and severe (19 to 31).
Secondary outcomes
• Improvement of LUTS measured by:
◦ sexual health,
◦ work status,
◦ mental health.
• Assessing side effects from pregabalin
Search methods for identification of studies
The references of all identified studies were inspected for more
trials. We had also handsearched systematic reviews and clinical
practice guidelines.
Data collection and analysis
Selection of studies
Two review authors (OMA and RLN) independently assessed relevant titles and abstracts identified by the literature search against
the predefined inclusion criteria. Full-text papers of the titles and
abstracts selected were further assessed for inclusion or exclusion.
Any problems were resolved by discussion and consensus.
Papers of in any language were considered for inclusion.
Data extraction and management
Two review authors (OMA and RLN) independently extracted
data from the included study using a predetermined data extraction form. Any disagreement was resolved by consensus. The authors of the included study were not contacted for clarification of
data or additional information as this was not needed.
Electronic searches
The following electronic databases were searched:
1. the Cochrane Central Register of Controlled Trials
(CENTRAL) (The Cochrane Library);
2. MEDLINE (1966 to 2012);
3. EMBASE (1980 to 2012);
4. ClinicalTrials.gov;
5. Google Scholar;
6. Web of Science;
7. Biosys Previews;
8. LILACS;
9. Health Technology Assessments (HTA);
10. Current Controlled Trials (www.controlled-trials.com/);
Assessment of risk of bias in included studies
The review authors (OMA and RLN) assessed the risk of bias
as described in the Cochrane Handbook for Systematic Reviews of
Interventions (Higgins 2011).
Factors that were assessed included:
1. sequence generation (i.e. was the allocation sequence
adequately generated?);
2. allocation sequence concealment (i.e. was allocation
adequately concealed?);
3. blinding (i.e. was knowledge of the allocated intervention
adequately prevented during the study?);
4
4. incomplete outcome data (i.e. were incomplete outcome
data adequately addressed?);
5. selective outcome reporting (i.e. are reports of the study free
of suggestion of selective outcome reporting?);
6. other potential sources of bias (i.e. was the study apparently
free of other problems that could put it at a high risk of bias?).
A judgment of ’yes’ indicated low risk of bias; ’no’ indicated high
risk of bias, and ’unclear’ indicated unclear or unknown risk of
bias.
Assessment of heterogeneity
Heterogeneity was not assessed as a meta-analysis was not conducted owing to only one included trial.
Assessment of reporting biases
Reporting biases were not assessed as a meta-analysis was not conducted owing to only one included trial.
Data synthesis
Measures of treatment effect
Review Manager 5 (RevMan 2011) was used to analyze data. Analyses were performed using an intention-to-treat (ITT) principle.
If we had performed a meta-analysis, data from individual trials
would have been combined when the interventions and controls
were similar. Dichotomous data would have been calculated as
risk ratios (RR) with 95% confidence intervals (95% CI). A fixedeffect model would have been used. The weighted mean difference
(WMD) with 95% CI would have been calculated for continuous
outcomes.
Unit of analysis issues
In addition to simple parallel group designs, variations such as
cluster-randomization and cross-over trials were to be analyzed;
however, no such trials were included.
Dealing with missing data
The authors of papers with missing data (studies, outcomes, summary data, individuals, measures of variance, or study level characteristics) were not contacted as no missing data were identified.
Patients who withdrew or dropped out of the study were considered as non responders and included into the failure group on an
ITT basis.
Data synthesis was not performed as a meta-analysis was not conducted owing to only one included trial.
Subgroup analysis and investigation of heterogeneity
A subgroup analysis was not conducted.
Sensitivity analysis
A sensitivity analysis was not performed as a meta-analysis was not
conducted owing to only one included trial.
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies.
See ’Characteristics of included studies’ and ’Characteristics of
excluded studies’.
Results of the search
A flow chart of the article selection process is displayed in Figure
1. The literature search yielded 153 articles, of which 139 articles
were excluded. Thirteen articles were excluded after reviewing the
full-text paper and only one article was included in this review.
5
Figure 1. Flow chart of article selection process.
Included studies
Only one study was found that compared pregabalin to a placebo
to improve patients’ symptoms of CP/CPPS (Pontari 2010).
Pontari 2010 conducted an RCT over 10 North American tertiary
care centres and included 324 patients between the ages of 19
to 78 years. The pregabalin and placebo groups were comparable
regarding age of the patients; the pregabalin group had a mean
age of 48 years (range 21 to 78 years) while the mean age in the
placebo group was 45.2 years (19 to 76 years) (P = 0.09). Also,
no difference was found when comparing race, educational level,
employment, and annual income (P = 0.17, P = 0.97, P = 0.25, and
P = 0.7, respectively). There was also no difference between the
two groups regarding ’years since first diagnosis’ (8.7 years versus
9.2 years) and ’years since first symptoms’ (10.3 years versus 9.9
years, respectively; P = 0.63).
The study was conducted with patients who had a minimum score
of 15 out of 43 on the NIH-CPSI.
During the six-week trial, the initial dose of pregabalin was 50 mg
three times daily for two weeks. It was then escalated to 100 mg
three times daily for a further two weeks, and again to 200 mg
three times daily for the final two weeks. Patients who developed
side effects were maintained on the pre-escalation dose.
See ’Characteristics of included studies’.
Excluded studies
Eight of the 13 articles were duplicates and so were removed.
Three of the studies were not RCTs (Johansen 2002; Pontari 2007;
Strauss 2010). One study was on nerve growth factor levels in CP/
CPPS (Watanabe 2011) and the last study was an RCT but on
transcutaneous electrical nerve stimulation (TENS) for CP/CPPS
rather than pregabalin (Sikiru 2008).
See ’Characteristics of excluded studies’.
Risk of bias in included studies
See ’Figure 2’ and ’Figure 3’.
6
Figure 2. ’Risk of bias’ graph: review authors’ judgments about each ’Risk of bias’ item presented as
percentages across all included studies.
Figure 3. ’Risk of bias’ summary: review authors’ judgments about each ’Risk of bias’ item for each included
study.
7
Allocation
The sequence generation was adequate in the included study; however, it was not clear how the allocation was concealed (Pontari
2010).
Blinding
The study was double blind.
(improvement: 5.0 points with pregabalin versus 1.6 points with
placebo; MD 1.3; 95% CI -0.5 to 3.2).
However, both the Global Response Assessment (GRA) and the
McGill Pain Questionnaire scores showed that there was more
improvement (less pain) in the pregabalin group compared to the
placebo group (GRA: 31.2% of patients improved versus 18.9% of
patients improved, respectively; RR 1.95; 95% CI 1.11 to 3.43);
McGill: 4.2-point improvement versus 1.7-point improvement,
respectively; MD -2.3; 95% CI -4.0 to -0.7).
Incomplete outcome data
There was a total of 11 patients who withdrew from the trial, eight
in the pregabalin group and three in the placebo group (P > 0.05).
Selective reporting
There were no indications of selective reporting in the included
study.
Other potential sources of bias
No other sources of bias were identified.
Effects of interventions
For the NIH-CPSI, there was no difference in clinical improvement (≥ 6 points) between the pregabalin and placebo groups
(47.2% versus 35.8%, respectively; RR 1.32; 95% CI 0.99 to
1.76).
However, there were significant differences in the final scores of
individual NIH-CP/CPPS domains between the pregabalin and
placebo groups compared to baseline scores. With regards to pain
there was a 3.2/21 point improvement in the pregabalin group
compared to 2.3/21 point improvement in the placebo group (MD
-1.0 points; 95% CI -2.00 to -0.04 points), urinary symptoms
improved by 1.2/10 points versus 0.7/10 points in the respective
groups (MD -0.70 points; 95% CI -1.0 to -0.02 points), and
quality of life improvement was 2.0/12 points versus 1.5/12 points
(MD -0.70 points; 95% CI -1.20 to -0.10 points).
Furthermore, there were varying results with the other assessment
tools used. There was no difference between the pregabalin and
placebo groups with regard to anxiety and depression assessment
(improvement: 2.4 points with pregabalin versus 1.9 points with
placebo; MD -0.70; 95% CI -2.00 to 0.07), sexual health assessment (improvement: 0.5 points with pregabalin versus 0.2 points
with placebo; MD -0.6; 95% CI -2.1 to 0.9), mental assessment
component of the Medical Outcomes Study 12-Item Short Form
Health Survey (MOS SF-12) (improvement: 3.2 points with pregabalin versus 1.8 points with placebo; MD 1.4; 95% CI -0.9 to
3.8), and the physical assessment component of the MOS SF-12
Side effects
A large number of patients (191/324; 59%) developed at least one
side effect related to pregabalin, although they were designated
as mild (24.6%) and moderate (24.4%). No-one reported serious
side effects.
There was no significant difference in the incidence of side effects
between the two groups (P = 0.4). In the pregabalin group, 18.3%
(40/218) of patients developed gastrointestinal disturbances compared to 18.9% (20/106) in the placebo group (P = 0.91; RR 0.97;
95% CI 0.60 to 1.58), while 6.9% (15/218) of patients developed
ocular/visual symptoms compared to 2.8% (3/106) (P = 0.08; RR
2.43; 95% CI 0.72 to 8.22), and 5.5% (12/218) of patients developed renal/genitourinary symptoms compared to 1.9% (2/106)
(P = 0.16; RR 3.03; 95% CI 0.67 to 13.79).
However there were more neurologic symptoms in the pregabalin
group compared to the placebo group (38.5% (84/218) versus
22.6% (24/106), respectively; P = 0.01; RR 1.7; 95% CI 1.15 to
2.51) and there was less pain in the pregabalin group compared to
the placebo group (17.4% (38/218) versus 33% (35/106), respectively; P = 0.003; RR 0.53; 95% CI 0.36 to 0.78). There was no
mention of specific neurologic symptoms; however, the authors
do mention that headaches were the predominant side effect in
each group but more significant in the placebo group with 4.6%
(10/218) of patients in the pregabalin group and 17% (18/106)
of patients in the placebo group (RR 0.27; 95% CI 0.13 to 0.56).
No explanation could be found as to why the placebo group had
more headaches.
DISCUSSION
Summary of main results
There was no significant evidence that pregabalin was better than
placebo in the overall NIH-CP/CPPS score. However, there was
significant improvement in the individual NIH-CPSI subscores,
8
favouring the pregabalin group. No difference was found between
the two groups with regard to anxiety and depression scores, sexual
health, and mental and physical assessment scores.
There was no difference between the pregabalin and placebo
groups with regards to adverse events. Although there was significantly less pain in patients who took pregabalin compared to
placebo, the presence of increased neurologic adverse events in just
six weeks in the pregabalin group questions the extended use of
pregabalin over longer periods of time.
Similarly to the authors of the RCT, we conclude that pregabalin
therapy is not superior to a placebo, though there were some biases
detected in the trial methodology. However, our interpretation of
the results agreed with their conclusion.
Agreements and disagreements with other
studies or reviews
Though this review could not show that pregabalin, a neuropathic
analgesic, was more effective than placebo for overall symptom
relief, pregabalin did improve overall pain symptoms, which supports the theory that CP/CPPS is neuropathic in nature as suggested in numerous publications (Miller 2002; Pontari 2005; Yang
2003; Yilmaz 2007).
No other systematic review was identified in the literature search.
AUTHORS’ CONCLUSIONS
Implications for practice
Overall completeness and applicability of
evidence
The included trial addressed the primary and secondary objectives
of this review, with relevant participants and interventions. However, a conclusive decision cannot be drawn from one trial. The one
included trial did calculate for power, had a less that 10% dropout rate, and was considered a well-conducted, double-blinded,
randomized placebo-controlled trial, and therefore their evidence
can be taken into consideration.
Quality of the evidence
The included study was a randomized, double-blind, placebo-controlled trial that included a representative portion of the population of the US. The quality of the study had low risk of bias.
Although a conclusive decision cannot be made from only one
included paper, there was evidence to suggest that pregabalin does
not improve overall CP/CPPS symptoms; however, pregabalin
might be of benefit for individual symptoms such as pain, urinary
symptoms, and overall quality of life. Pregabalin did cause adverse
effects in a large percentage of men.
Implications for research
Further trials are required to confirm whether or not pregabalin
has a role in the management of CP/CPPS. However, trials should
measure the benefits against the risk of side effects with taking
these medications over long periods of time to avoid the replacement of one group of symptoms with another. Therefore, further
double-blind, placebo-controlled, randomized trials are required
specifically focused on symptom relief based on etiology, in addition to a prolonged follow-up period. Trials comparing different
analgesics to pregabalin, in addition to comparisons with other
neuropathic analgesics such as gabapentin and amitriptyline, will
add more information and clarify whether neuropathic analgesics
have a role in CP/CPPS.
Potential biases in the review process
The potential risk of this review is that it only included one single
trial. This does not reflect the methodology of the review as the
literature was meticulously searched for studies by two independent review authors.
ACKNOWLEDGEMENTS
The Prostatic Diseases and Urologic Cancers Review Group.
9
REFERENCES
References to studies included in this review
Pontari 2010 {published data only}
Pontari M, Krieger J, Litwin M, White P, Anderson R,
McNaughton-Collins M, et al.Pregabalin for the treatment
of men with chronic prostatitis/chronic pelvic pain
syndrome. Archives of Internal Medicine 2010;170(17):
1586–93.
References to studies excluded from this review
Johansen 2002 {published data only}
Johansen T, Weidner W. Understanding chronic pelvic pain
syndrome. Current Opinion in Urology 2002;12:63–7.
Pontari 2007 {published data only}
Pontari M, Joyce G, Wise M, McNaughton-Collins M, and
the Urologic Diseases in America Project. Prostatitis. The
Journal of Urology 2006;177:2050–7.
Sikiru 2008 {published data only}
Sikiru L, Shmaila H, Muhammed S. Transcutaneous
electrical nerve stimulation (TENS) in the symptomatic
management of chronic prostatitis/chronic pelvic pain
syndrome: a placebo-control randomized trial. International
Brazilian Journal of Urology 2008;34:708–14.
CPCRN 2004
The Chronic Prostatitis Collaborative Research Network.
The economic impact of chronic prostatitis. Archives of
Internal Medicine 2004;164:1231–6.
Dworkin 2005
Dworkin R, Kirkpatrick P. Pregabalin. Nature Review Drug
Discovery 2005;4:455–6.
Dworkin 2010
Dworkin R, O’Connor AB, Audette J, Baron R, Gourlay
GK, Haanpää ML, et al.Recommendations for the
pharmacological management of neuropathic pain: an
overview and literature update. Mayo Clinical Proceedings
2010;85(3):S3–14.
Gottsch 2010
Gottsch HP, Yang CC, Berger RE. A pilot study of
botulinum toxin A for male chronic pelvic pain syndrome.
Scandinavian Journal of Urology and Nephrology 2010;
Vol. 45, issue 1:72–6. [PUBMED: 21062115]
Higgins 2011
Higgins JPT, Green S (editors). Chapter 8: Assessing
risk of bias in included studies. Cochrane Handbook
for Systematic Reviews of Interventions Version 5.1.0
[updated March 2011]. The Cochrane Collaboration,
2011. Available from www.cochrane-handbook.org.
Strauss 2010 {published data only}
Strauss A, Dimitrakov J. New treatments for chronic
prostatitis/chronic pelvic pain syndrome. Nature Review
Urology 2010;7:127–35.
Jain 2005
Jain KK. Clinical summary: pregabalin, 2011.
www.medlink.com/medlinkcontent.asp (accessed 15 June
2012).
Watanabe 2011 {published data only}
Watanabe T, Inoue M, Sasaki K, Araki M, Uehara S,
Monden K, et al.Nerve growth factor level in the prostatic
fluid of patients with chronic prostatitis/chronic pelvic pain
syndrome is correlated with symptom severity and response
to treatment. BJU International 2011;108(2):248–51.
Krieger 1999
Krieger J, Nyber L, Nickel JC. NIH consensus definition
and classification of prostatitis. Journal of the American
Medical Association 1999;282(3):236–7.
Additional references
Arnold 2010
Arnold L, Mease P, Silverman S. Pregabalin: an alpha2delta ligand for the management of fibromyalgia. American
Journal of Management and Care 2010;16:S138–43.
Bartoletti 2007
Bartoletti R, Mondaini N, Pavone C, Dinelli N, Prezioso
D. Introduction to chronic prostatitis and chronic pelvic
pain syndrome (CP/CPPS). Archivio Italiano di Urologia e
Andrologia 2007;79(2):55–7.
Cappuzzo 2009
Cappuzzo K. Treatment of postherpetic neuralgia: focus on
pregabalin. Clinical Interventions in Aging 2009;4:17–23.
Collins 1998
Collins M, Stafford R, O’Leary M, Barry M. How common
is prostatitis? A national survey of physician visits. The
Journal of Urology 1998;159:1224–8.
Litwin 1999
Litwin M, McNaughton-Collins M, Fowler FJ Jr, Nickel
JC, Calhoun EA, Pontari MA, et al.The National Institutes
of Health Chronic Prostatitis Symptom Index: development
and validation of a new outcome measure. The Journal of
Urology 1999;162:369–75.
Magri 2010
Magri V, Wagenlehner F, Perletti G, Schneider S, Marras E,
Naber KG, et al.Use of the UPOINT chronic prostatitis/
chronic pelvic pain syndrome classification in European
patient cohorts: sexual function domain improves
correlations. The Journal of Urology 2010;184:2339–45.
McNaughton Collins 2008
McNaughton Collins M, Wilt T. Allopurinol for chronic
prostatitis. Cochrane Database of Systematic Reviews 2008,
Issue 4. [DOI: 10.1002/14651858.CD001041]
Miller 2002
Miller LJ, Fischer KA, Goralnick SJ, Litt M, Burleson
JA, Albertsen P, et al.Nerve growth factor and chronic
prostatitis/chronic pelvic pain syndrome. Urology 2002;59
(4):603–8.
10
Nickel 2001
Nickel JC, Downey J, Hunter D, Clark J. Prevalence of
prostatitis-like symptoms in a population based study
using the National Institutes of Health Chronic Prostatitis
Symptom Index. Journal of Urology 2001;165:842–5.
Online Symptom Index
Chronic Prostatitis Collaborative Research Network. NIH
Chronic Prostatitis Symptom Index. www.prostatitis.org/
symptomindex.html (accessed 15 June 2012).
Pontari 2005
Pontari M, McNaughton-Collins M, O’Leary MP, Calhoun
EA, Jang T, Kusek JW, et al.A case-control study of risk
factors in men with chronic pelvic pain syndrome. BJU
International 2005;96(4):559–65.
RevMan 2011
The Nordic Cochrane Centre, The Cochrane Collaboration.
Review Manager (RevMan). 5.1. Copenhagen: The Nordic
Cochrane Centre, The Cochrane Collaboration, 2011.
Reynard 2006
Reynard J, Brewster S, Biers S. Oxford Handbook of Urology.
1st Edition. New York: Oxford University Press, 2006.
Roberts 1998
Roberts RO, Lieber MM, Rhodes T, Girman CJ, Bostwick
DG, Jacobsen SJ. Prevalence of a physician-assigned
diagnosis of prostatitis: the Olmsted County study of
urinary symptoms and health status among men. Urology
1998;51(4):578–84.
Weiss 2001
Weiss R, George N, O’Reilly P. Comprehensive Urology. Vol.
1, London: Mosby, 2001. [: ISBN: 0723429499]
Yang 2003
Yang CC, Lee JC, Kromm BG, Ciol MA, Berger RE. Pain
sensitization in male chronic pelvic pain syndrome: why are
symptoms so difficult to treat?. Journal of Urology 2003;170
(3):823–7.
Yilmaz 2007
Yilmaz U, Liu YW, Berger RE, Yang CC. Autonomic
nervous system changes in men with chronic pelvic pain
syndrome. Journal of Urology 2007;177:2170–4.
∗
Indicates the major publication for the study
11
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Pontari 2010
Methods
Randomized, placebo-controlled, double-blind, multi centered
Participants
324 patients ages 19 to 78 years with CP/CPPS
Diagnosis based on a minimum score of 15 out of 43 on the NIH-CPSI
Inclusion criteria: at least 18 years of age, pain/discomfort in the pelvic region during at
least 3 of the last 6 months, and with a minimum score of 15 on the NIH-CPSI
Exclusion criteria: calculated creatinine clearance < 60 mL/minute/1.73 m2 , platelet
count < 100,000 x 103 /µL, allergy to any anti-seizure medication, known sensitivity to
pregabalin, treatment with thiazolidine or antidiabetic agents, New York Heart Association class III or IV congestive heart failure, history of thrombocytopenia or bleeding
diathesis, and history of alcohol abuse
Interventions
Patients were divided into 2 groups to receive either pregabalin or a placebo for 6 weeks.
Initial dose of pregabalin was 50 mg 3 times daily for 2 weeks, followed by 100 mg 3
times daily for 2 weeks, followed by 200 mg 3 times daily for 2 weeks. Patients who
developed side effects were maintained on the pre-escalation dose
Outcomes
Primary outcome: improvement in the NIH-CPSI score of at least 6 points from baseline
Secondary outcomes: sub scores of the NIH-CPSI (pain 0 to 21, urinary symptoms 0 to
10, and quality of life 0 to 12), GRA (7-question patient self-reported assessment that
measures change in symptoms, i.e. improvement, no change, or deterioration where 0
is no change), the McGill Pain Questionnaire (0 to 45; 0 = least pain), the MOS SF12 which was also divided into physical (0 to 100) and mental (0 to 50) component
summary scores (0 = worse quality of life), HADS (0 to 42; the higher the number the
more anxiety and depression), and SHIM (1 to 25 higher scores indicating better sexual
function)
Adherence to treatment was calculated by capsule count at 2-, 4-, and 6-week follow-up
Notes
11 patients withdrew from the trial, 8 from the pregabalin group and 3 from the placebo
group
The participants were included in the intent-to-treat analysis
Risk of bias
Bias
Authors’ judgement
Random sequence generation (selection Low risk
bias)
Support for judgement
The authors explained that participants
were randomly assigned 2:1 randomizations via a centrally controlled Web-based
data management system to group patients
using a permuted block randomizations
procedure with randomly assigned block
sized of 3, 6, and 9
12
Pontari 2010
(Continued)
Allocation concealment (selection bias)
High risk
No report of concealment
Blinding (performance bias and detection Low risk
bias)
All outcomes
The authors report that the Investigators
and participants were unaware of treatment
assignment
Incomplete outcome data (attrition bias)
All outcomes
High risk
The authors report that there were patients
who withdrew and that they conducted an
intention-to-treat analysis. However in the
final analysis table the author states that
fewer patients were analyzed than were included, with no mention as to why there
were fewer patients
Selective reporting (reporting bias)
Low risk
There were no indications of selective reporting
Other bias
Low risk
No other sources of bias could be identified
CP/CPPS: chronic prostatitis/chronic pelvic pain syndrome; GRA: Global Response Assessment; HADS: Hospital Anxiety and Depression Scale; MOS SF-12: Medical Outcomes Study 12-Item Short Form Health Survey; NIH-CPSI: National Institutes of Health
Chronic Prostatitis Symptom Index; SHIM: Sexual Health Inventory for Men.
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Johansen 2002
Not an RCT or a study for pregabalin treatment
Pontari 2007
Not an RCT or a study on pregabalin treatment
Sikiru 2008
An RCT but on TENS for CP/CPPS rather than pregabalin
Strauss 2010
Not an RCT or a study for pregabalin treatment
Watanabe 2011
Study on nerve growth factor levels in prostatic fluid, not on pain control
CP/CPPS: chronic prostatitis/chronic pelvic pain syndrome; TENS: transcutaneous electrical nerve stimulation.
13
DATA AND ANALYSES
This review has no analyses.
HISTORY
Protocol first published: Issue 4, 2011
Review first published: Issue 8, 2012
CONTRIBUTIONS OF AUTHORS
Both OMA and RLN assessed relevant papers and abstracts, extracted data, assessed the risk of bias, and contributed to writing the
review.
DECLARATIONS OF INTEREST
None known.
SOURCES OF SUPPORT
Internal sources
• Prostatic Diseases and Urologic Cancers Group, USA.
External sources
• No sources of support supplied
INDEX TERMS
Medical Subject Headings (MeSH)
Analgesics [∗ therapeutic use]; Chronic Disease; Pelvic Pain [∗ drug therapy]; Prostatitis [∗ drug therapy]; Randomized Controlled Trials
as Topic; gamma-Aminobutyric Acid [∗ analogs & derivatives; therapeutic use]
MeSH check words
Humans; Male
14

Pregabalin for chronic prostatitis (Review) Aboumarzouk OM, Nelson RL The Cochrane Library

Transcription

Similar documents

Pregabalin for the Treatment of Men With Chronic

A PROSPECTIVE, RANDOMIZED, PLACEBO CONTROLLED, DOUBLE-

HealthTrax Brochure

J UI UroToday International Journal

Document 6429207

Clinical Research Review Clinical Studies Evaluating Herbs

Pain Management: Pain is inevitable. Suffering is

Penile pain- “What`s wrong, doc?”

Document 6474174

, pregabalin Medication Policy Manual