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Wkw 2450 sator-katzenschlagerSator-Katzenschlager et al., Gabapentin and amitriptyline causing chronic pelvic pain WIENER KLINISCHEWOCHENSCHRIFTThe Middle European Journalof Medicine Wien Klin Wochenschr (2005) 117/21–22: ■–■DOI 10.1007/s00508-005-0464-2 Printed in Austria Chronic pelvic pain treated with gabapentin and amitriptyline:
A randomized controlled pilot study
Sabine M. Sator-Katzenschlager1, Gisela Scharbert1, H■■■ G. Kress1, N■■■ Frickey1,
A■■■ Ellend2, A■■■ Gleiss3, and Sibylle A. Kozek-Langenecker1
1 Department of Anesthesiology and Intensive Care (B), Pain Clinic, Medical University of Vienna, Vienna, Austria 2 Department of Gynecology and Obstetrics, Medical University of Vienna, Vienna, Austria 3 Core Unit for Medical Statistics and Informatics, Medical University of Vienna, Vienna, Austria Received March 22, 2005, accepted after revision August 29, 2005 Springer-Verlag 2005 Konklusion: Diese Ergebnisse legen nahe, dass die Pharmakotherapie mit dem Antikonvulsivum Gabapentindie Behandlung von chronischen Unterbauchschmerzen Zusammenfassung. Einleitung: Gegenstand der
bei ambulanten Patientinnen verbessert.
Studie war der Vergleich der Wirksamkeit und Verträg-lichkeit von Gabapentin bzw. Amitriptylin allein mit derKombination der beiden Medikamente bei chronischen Summary. Background: The aim of this study was to
Unterbauchschmerzen (chronic pelvic pain, CPP).
compare the efficacy and side effects of gabapentin, Methoden: 56 weibliche Patientinnen mit chronischen amitriptyline, and their combination in women with chron- Unterbauschmerzen wurden bei der prospektiven, rando- ic pelvic pain.
misierten open-label-Studie mit einem 2-jährigem follow- Methods: In this open-label, prospective, randomized up an der Schmerzambulanz der Universitätsklinik Wien, trial 56 women with chronic pelvic pain were investigated Österreich, eingeschlossen. Wenn die Schmerzintensität with a two-year follow-up at the Vienna medical university trotz analgetischer Therapie mit dem Nichtopioid Metami- hospital. If pain intensity assessed by a visual analog zol und einem schwachen Opioid gemessen auf der visu- scale (VAS) was 5 or more (0 = no pain, 10 = maximal ellen Analogskala (VAS) bei 5 oder darüber lag (0 = kein pain), despite analgesic therapy using the nonopioid drug Schmerz, 10 = schlimmster vorstellbarer Schmerz), wur- metamizol together with weak opioids, patients were ran- den die Patientinnen randomisiert einem der drei Be- domized to receive gabapentin (n = 20), amitriptyline handlungsarme zugeteilt (Gabapentin, n = 20; Amitripty-
(n = 20), or a combination of both drugs (n = 16). Doses of lin, n = 20 oder beides, n = 16). Die Medikamentengaben gabapentin and amitriptyline were increased to maximum von Gabapentin bzw. Amitriptylin wurden auf eine täg- daily doses of 3600 mg and 150 mg, respectively, until liche Dosis von 3600 mg bzw. 150 mg gesteigert, bis eine sufficient pain relief or the occurrence of side effects. VAS suffiziente Schmerzerleichterung erreicht war oder uner- and side effects were evaluated before treatment and at wünschte Nebenwirkungen auftraten. VAS-Werte wurde 1, 3, 6, 12 and 24 months afterwards.
vor Beginn der Behandlung und 1, 3, 6, 12 und 24 Results: All patients experienced significant pain re- Monate danach erhoben.
lief during the observation period. However, after 6, 12 Ergebnisse: Alle Patientinnen erfuhren während des and 24 months, pain relief was significantly better in Beobachtungszeitraumes eine signifikante Schmerzre- patients receiving gabapentin either alone or in combina- duktion. Dennoch war die Schmerzreduktion bei Patien- tion with amitriptyline than in patients receiving mono- tinnen, die Gabapentin allein oder in Kombination mit therapy with amitriptyline (gabapentin: 0 months: 7.7 ± Amitriptylin erhalten hatten, signifikant höher als unter 1.5, 6 months: 1.6 ± 0.9, 12 months: 1.5 ± 0.9, 24 months: Monotherapie mit Amitriptylin (Gabapentin: 0: 7.7 ± 1.5, 6: 1.9 ± 0.9; amitriptyline: 0 months: 7.3 ± 1.5, 6 months: 1.6 ± 0.9, 12: 1.5 ± 0.9, 24: 1.9 ± 0.9; Amitriptylin: 0: 7.3 ± 2.2 ± 1.6, 12 months: 2.2 ± 1.6, 24 months: 3.4 ± 0.9; 1.5, 6 : 2.2 ± 1.6, 12: 2.2 ± 1.6, 24: 3.4 ± 0.9; Amitriptylin/ amitriptyline/gabapentin: 0 months: 7.6 ± 0.8, 6 months: Gabapentin: 0: 7.6 ± 0.8, 6: 1.3 ± 0.9, 12: 1.7 ± 1.0, 24: 1.3 ± 0.9, 12 months: 1.7 ± 1.0, 24 months: 2.3 ± 0.9).
2.3 ± 0.9). Unerwünschte Nebenwirkungen traten signifi- Side effects were lower in the gabapentin group than in kant seltener in der Gabapentin-Gruppe auf als in den the two other groups, the difference reaching statistical beiden anderen Gruppen (p < 0.05).
significance after three months (P < 0.05).
Sator-Katzenschlager et al., Gabapentin and amitriptyline causing chronic pelvic pain Conclusion: Gabapentin alone or in combination with Materials and methods
amitriptyline is better than amitriptyline alone in the treat- Women consecutively entering treatment for chronic pel- ment of female chronic pelvic pain.
vic pain persisting longer than six months were enrolled in this Key words: Chronic pelvic pain, gabapentin, amitrip-
study at our outpatient pain center between October 2000 and October 2002. Local ethics committee approval was obtainedand patients provided informed consent to their participationprior to data analysis. Before beginning treatment, patients underwent detailed and standardized gynecological, urological, Pelvic pain in women may be induced by gynecolog- neurological, internal and psychological evaluation according ical, urological, gastrointestinal, musculoskeletal or psy- to the protocol of our outpatient pain center.
chiatric pathologies , and can be of visceral and/or First-line pain therapy consisted of 1000 mg metamizol neuropathic origin [2–5]. Recommended state-of-the-art four times daily, together with 100 mg of the weak opioid treatments for visceral and neuropathic pain differ consid- tramadol twice daily, and with rescue medication tramadol erably [4, 7–9]. Tricyclic antidepressants and anticonvul- 50 mg up to six times daily (Fig. 1). Pain intensity was scored sive drugs have emerged as effective standard treatment using a visual analog scale (VAS; 0 = no pain, 10 = worst pain options for neuropathic pain : amitriptyline is an effec- imaginable). The quality of pain was described by the patient as tive tricyclic antidepressant, but side effects often limit its burning, lancinating, electrifying or searing (neuropathic pain), clinical use [10, 11]; gabapentin [1-(aminomethyl)cyclo- or a combination of neuropathic and nociceptive pain qualities(dull, aching, cramping, vice-like sensations: i.e. nociceptive hexanacetic acid] is a structural analog of γ-aminobutyric pain of somatic or visceral origin). Study participants were re- acid, which was initially introduced in 1994 as an anticon- evaluated after a week. If pain intensity was at least VAS 5, the vulsive drug [12–14], and has been reported to be well dose of tramadol was increased to 200 mg twice daily. Patients tolerated and effective in the treatment of various chronic were eligible for the next step if, despite medication, their pain conditions, particularly in neuropathic pain [13, 15].
persisting pain intensity was at least VAS 5 after the second To date, no study has determined the efficacy and safety week of treatment.
of antineuropathic therapy in patients with chronic pelvic We tried to achieve a balanced study design by randomiza- pain. Accordingly, we compared the effects of amitrip- tion. Patients were randomly allocated into the gabapentin tyline and gabapentin and their combination in women group (Neurontin®, Goedecke AG, Berlin, Germany), the ami- with chronic pelvic pain refractory to antinociceptive triptyline group (Saroten®, Lundbeck, Kopenhagen, Denmark) treatment for visceral pain.
or the combination group. Treatments with metamizol and tra- Fig. 1. Trial profile
Sator-Katzenschlager et al., Gabapentin and amitriptyline causing chronic pelvic pain madol were discontinued upon randomization. Exclusion crite- contrast of all three pair-wise group comparisons was comput- ria for antineuropathic treatment with amitriptyline and gaba- ed for each of the five time-points, and the five resulting pentin were renal, hepatic, cardiovascular or psychiatric dis- P-values were corrected by the Bonferroni-Holm method. For orders. In order to avoid unwanted side effects, the dose of each time-point that was considered significant in this way, the amitriptyline was carefully increased from an initial dose of three separate group comparisons were computed without fur- 25 mg per day up to a maximum dose of 150 mg per day in ther correction (Fisher's LSD principle). For both drugs, the 25 mg increments each week until sufficient pain relief, or the dose pattern over time was assessed using the Cochran-Mantel- occurrence of side effects such as somnolence, dizziness, ortho- Haenszel statistic (test against non-zero correlation over strata) static hypotension, palpitations, dry mouth and weight gain.
based on rank scores and stratified for treatment groups. For the Similarly, the dose of gabapentin was carefully increased from time-points 12 and 24 months of treatment, the number of 300 mg per day up to a maximum dose of 3600 mg per day in different pain qualities was compared between treatment 300 mg increments each week until sufficient pain relief, or the groups using the Kruskal-Wallis test, stratified for the number occurrence of side effects such as dizziness, somnolence, ede- of different pain qualities before treatment. At baseline and at ma and ataxia. Exclusion criteria were the concomitant admin- 12 and 24 months, the incidences of each single pain quality istration of strong opioids, nonsteroidal anti-inflammatory were compared between treatment groups using Fisher's exact drugs, benzodiazepines, capsaicin or skeletal muscle relaxants.
test. The incidences of side effects were compared at each time- Intensity and quality of the pain and side effects of the point by a comparison between all three treatment groups of the medication were routinely evaluated at the weekly visit to the incidence that any side effect occurred (Fisher's exact test); a pain center for the first three months, and then at least once a Bonferroni-Holm correction was performed for the five time- month for 24 months. If pain relief was maintained for three points and corrected P-values are given. For overall tests that months, doses of amitriptyline and gabapentin were carefully were significant after this correction, the three pair-wise com- decreased and adjusted to maintain VAS below 3.
parisons were computed (again using Fisher's exact test) with- Demographic, social and economic data were documented.
out further correction.
All patients also received active and passive physical therapy, SAS Version 8.2 (SAS Institute Inc., Cary, NC, USA, transcutaneous electrical nerve stimulation and/or acupuncture 2001) was used for all computations.
at the beginning of the study. The use of adjuvant pain therapieswas documented. Patients' overall satisfaction with their pain treatment was determined at the end of the study period.
Patient enrolment Seventy-eight patients with chronic pelvic pain en- tered pain therapy at our pain clinic. In 56 patients, pain Data are presented as means ± standard deviation (SD) or intensities persisted above VAS 5 after the first two weeks as counts and percent of total. P-values < 0.05 were considered of treatment with metamizol and tramadol. There was no to be statistically significant. In a preliminary analysis the significant difference in pain history and demographic differences from baseline values were tested against being dif- data between patients with VAS > 5 and those with VAS ferent from zero at each time-point in each of the three treat- < 5. In the 56 patients with greater pain intensity, metam- ment groups. For this purpose, a repeated measurements analy- izol and tramadol were replaced by gabapentin (n = 20), sis of variance was performed with differences from baseline asoutcome and age as a covariate for adjustment. The resulting 15 amitriptyline (n = 20), or a combination of both drugs P-values were rigorously corrected using the method of Bon- (n = 16) (Fig. 1). During the study period of 24 months, ferroni-Holm. For the main analysis, i.e. for assessing the seven patients discontinued pain treatment: in the gaba- differences of VAS levels between groups at the five time- pentin group, one patient was not compliant and two points, an analysis of covariance for repeated measurements experienced severe side effects which necessitated dis- was performed, with covariate age, and also with the baseline continuation of oral medication; in the amitriptyline value as covariate. Time-specific group comparisons were cor- group, one patient dropped out because of insufficient rected for multiplicity using a two-step procedure. The overall pain reduction and two experienced severe side effects; in Table 1. Demographic and socioeconomic data
Stable partnership Working full time Data are presented as means ± SD or as numbers (percent of totals). AMI amitriptyline, GBP gabapentin.
Sator-Katzenschlager et al., Gabapentin and amitriptyline causing chronic pelvic pain Table 2. Patients' characteristics
Right lower abdomen Left lower abdomen Middle lower abdomen Bladder distension Intestinal surgery Urogenital infection Three times or more Concomitant disease with MRI-verified pathology Adjuvant pain therapies Data are presented as numbers (percent of totals). AMI amitriptyline; GBP gabapentin; MRI magnet resonance imaging;TENS transcutaneous electrical nerve stimulation.
the combination group, one patient experienced severe Effects of antineuropathic therapy on the intensity side effects. Accordingly, 49 of the 56 patients were in- and quality of pain cluded in the final data analysis.
The course of pain intensity is shown in Fig. 2. There Demographic and socio-economic data was no difference between the groups in the initial VASscore (gabapentin group 7.7 ± 1.5, amitriptyline group At the time of enrolment, there were no relevant 7.3 ± 1.5, amitriptyline/gabapentin group 7.6 ± 0.8). All differences in age, weight, height or socio-economic sta- patients experienced significant pain relief at all investi- tus between the three treatment groups (Table 1).
gated time-points compared with the pain score beforetreatment (all uncorrected P-values < 0.0001). However, Pain history after 6, 12 and 24 months, pain relief was significantly Mean duration of pain before enrolment was 5.9 ± 2.4 greater in patients receiving gabapentin either alone or in years, without any difference between the three groups.
combination with amitriptyline than in patients on ami- The majority of patients had experienced various treat- triptyline alone.
ments before entering our study, including analgesic The mean daily doses of antineuropathic drugs re- drugs, trigger-point infiltrations, transcutaneous electrical quired for pain relief in the absence of side effects were nerve stimulation, as well as both active and passive decreased after three months, within the first six months physiotherapy including massage, warmth and galvaniza- of treatment (Table 3). In all groups, dosages could be tion. During the study period of 24 months, all patients reduced over time until 24 months of treatment. There was received active and passive physiotherapy and psycho- a significant negative correlation between time and dosage therapy (Table 2). The location of pain (abdomen, peri- (amitriptyline P = 0.003, gabapentin P < 0.001).
neum, anus, vulva, vagina or low back) and the mean At 24 months of antineuropathic pharmacotherapy, number of prior surgical interventions were similar in all there was no significant difference between the groups in groups (Table 2).
the number of different pain qualities corrected for base- Sator-Katzenschlager et al., Gabapentin and amitriptyline causing chronic pelvic pain Fig. 2. Pain intensity under gabapentin (GBP), amitriptyline (AMI) and their combination. Data are presented as means ± SD of
subjective visual analog scales (VAS) scores ranging from 0 (= no pain) to 10 (= worst pain imaginable). * AMI group versus GBP
group; # AMI group versus AMI/GBP group, and GBP group versus AMI/GBP group, significant at the 5% level (corrected for
line values (P = 0.112); however, the same analysis months: 0.071, 0.024, 0.067, 0.115, 0.115). There was no showed a significantly different number of pain qualities significant difference between the groups in the inci- after 12 months (P = 0.018). There was no group differ- dence of severe side effects, requiring discontinuation of ence in the incidences of single pain qualities at the differ- treatment (gabapentin n = 2; amitriptyline n = 2; amitrip- ent time-points (baseline, 12 and 24 months) (Table 4).
tyline/gabapentin n = 1).
Side effects of antineuropathic therapy The incidences of side effects are shown in Fig. 3.
In the present study the therapeutic effects of gaba- The incidence of minor side effects which prevented a pentin, amitriptyline, and the combination of amitrip- further increase in the daily drug dosage was lower in tyline/gabapentin were compared in 56 adult female the gabapentin group than in the two other groups patients with chronic pelvic pain refractory to surgical throughout the observation period (corrected P-values intervention and antinociceptive pharmacotherapy with for the overall three-groups comparison at 1, 3, 6, 12, 24 metamizol and tramadol. All patients experienced signifi- Table 3. Mean daily doses of antineuropathic drugs
Treatment duration 59.23 ± 23.52 mg 1559.00 ± 524.63 mg 75.50 ± 33.91 mg (10–150)1487.50 ± 586.37mg(900–3200) 63.89 ± 19.56 mg 1788.24 ± 427.02 mg 76.67 ± 30.56 mg (10–150)1473.33 ± 113.59 mg(900–2400) 66.18 ± 17.55 mg 1731.25 ± 442.29 mg 65.00 ± 18.41 mg (25–150)1393.33 ± 361.48 mg(900–1800) 1287.50 ± 537.74 mg 66.67 ± 22.49 mg (25–125)886.67 ± 718.99 mg(0–1800) 52.94 ± 24.82 mg (0–75)480.0 ± 421.22(0–1200 ) Data are presented as means ± SD and range (minimum–maximum). AMI amitriptyline, GBP gabapentin.
Sator-Katzenschlager et al., Gabapentin and amitriptyline causing chronic pelvic pain Table 4. Pain qualities
Fisher's exact test: all uncorrected P > 0.06. AMI amitriptyline; GBP gabapentin.
cant pain relief during the observation period of 24 typical qualities of neuropathic pain conditions: these months; however, pain relief was significantly greater in include the persistent burning and convulsive quality of patients receiving gabapentin either alone or in combina- the pain, allodynia and hyperpathia, as well as the fre- tion with amitriptyline than in patients on amitriptyline quent absence of morphological pathology. The genesis alone. To our knowledge, this is the first study to compare of neuropathic pain seems to be complex, involving both the efficacy of the antineuropathic drugs gabapentin and peripheral and central nervous mechanisms [13, 21, 22].
amitriptyline in women with chronic pelvic pain. In con- Peripheral nerves generate ectopic discharges by increas- trast to our results, a study in diabetic patients with neuro- ing the activation of sodium channels [6, 12, 13], and this pathic pain found that gabapentin and amitriptyline gave process is likely to be responsible for spontaneous, par- similar degrees of pain relief , although others have oxysmal pain in neuropathy. The activation of N-methyl- also observed the superiority of gabapentin over amitrip- D-aspartate (NMDA) receptors and an imbalance be- tyline in diabetic neuropathic pain .
tween the inhibitory and excitatory circuitry at the spinal A few studies have compared amitriptyline versus level contribute to central sensitization of the spinal cord placebo and gabapentin versus placebo in patients with dorsal-horn neurons in response to abnormal, repetitive chronic pelvic pain [18, 19]. Amitriptyline has been rec- peripheral nociceptive inputs following nerve or tissue ommended as the treatment of choice by some authors injury . Central sensitization plays a key role in both , whereas others have reported disappointing results the development and maintenance of neuropathic pain . Similarly, gabapentin failed to improve genitouri- symptoms [12, 13]. In our patients, gabapentin was more nary-tract pain in some studies , but has been proven effective than amitriptyline in ameliorating neuropathic successful in the treatment of diabetic neuropathy, post- burning or spontaneous, paroxysmal pain. Interestingly, herpetic neuropathy, neuropathic pain associated with the effect of gabapentin does not seem to interact with carcinoma, multiple sclerosis, genitourinary-tract pain any of these known mechanisms of neuropathic pain and vulvodynia by others . Although spontaneous, [12, 13]. Further studies are required to determine which paroxysmal pain of burning or lancinating quality and mechanisms are involved in the genesis of chronic pelvic allodynia to cold and tactile stimuli respond to gabapen- pain and at which site gabapentin and amitriptyline exert tin, dull, aching pain and hyperalgesia are less likely to their pain-relieving effect, as demonstrated by our results do so. Our study confirms that chronic pelvic pain has and by others [17–19, 21].
Fig. 3. Side effects of gabapentin (GBP), amitriptyline (AMI) and their combination. Side effects that prevented a further increase
in the daily drug dosage were lower in the gabapentin group than in the two other groups throughout the observation period, and
significantly lower after 3 months. Data are presented as means ± SD. * AMI group versus GBP group; # GBP group versus AMI/
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Journal of Antimicrobial Chemotherapy (2002) 49, 999–1005DOI: 10.1093/jac/dkf009 Risk factors associated with nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection including previous use of antimicrobials Eileen M. Graffunder* and Richard A. Venezia Department of Epidemiology MC-45, Albany Medical Center Hospital, 43 New Scotland Avenue, Albany,