- Email: [email protected]
Influence of antipsychotic medication on pain perception in schizophrenia
Psychiatry Research 142 (2006) 151 – 156 www.elsevier.com/locate/psychres
Influence of antipsychotic medication on pain perception in schizophrenia Thomas Jochum, Andrea Letzsch, Wolf Greiner, Gerd Wagner, Heinrich Sauer, Karl-Ju¨rgen Ba¨r * Department of Psychiatry, Friedrich-Schiller-University of Jena, Philosophenweg 3, 07743 Jena, Germany Received 20 October 2004; accepted 17 September 2005
Abstract A number of clinical observations indicate that pain processing might be disturbed in psychotic disorders such as schizophrenia. Only a few studies have investigated pain perception in schizophrenia. The main objective of this study was the investigation of thresholds of warmth perception (WP), thermal pain onset (TPO) and thermal pain tolerance (TPT) in acute schizophrenic patients and the influence of antipsychotic medication on the patients’ responses. We investigated 23 schizophrenic subjects who had been not received antipsychotic treatment for 8 weeks, and we then reassessed them 3 days later after the introduction of neuroleptics. Acute symptoms of schizophrenia were measured using the Scales for the Assessment of Positive and Negative Symptoms. Thresholds were determined by a contact thermode on both volar wrists. Schizophrenic patients showed significantly increased thresholds of WP and TPO relative to healthy controls. Antipsychotics did not alter pain thresholds. We found no correlation between pain perception and psychometric scales. Our findings demonstrate altered warmth and heat pain perception in acute schizophrenia. We believe that our findings can be attributed to information-processing abnormalities of the disorder and that they are not specific to pain processing, per se, since both WP and TPO were significantly different. Future studies should evaluate attentional deficits in schizophrenia in relation to pain perception. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Cognition; Neuroleptic treatment; Pain; Perception; Schizophrenia; Threshold
1. Introduction
* Corresponding author. Tel.: +49 3641 935282; fax: +49 3641 936217. E-mail address: [email protected] (K.-J. Ba¨r).
A number of clinical observations indicate that pain processing is disturbed in psychotic disorders such as schizophrenia. For example, schizophrenic patients may suffer from peritonitis, severe burns, fractures or myocardial infarction and show only minor indications of pain (Bickerstaff et al., 1988;
0165-1781/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2005.09.004
152
T. Jochum et al. / Psychiatry Research 142 (2006) 151–156
Rosenthal et al., 1990; Jakubaschk and Boker, 1991). It is noteworthy that this clinical phenomenon of pain insensitivity in schizophrenia has been particularly described by surgeons and anesthesiologists since they had to treat life-threatening sequels. Moreover schizophrenic patients are very rarely found in populations of chronic pain patients and are seldom known to suffer from post-puncture headache or migraine (Dworkin, 1994). Conversely, schizophrenic patients can present with bizarre sensory complaints (Huber, 1957) such as bpins and needlesQ in a sub-syndrome of schizophrenia called coenesthesia (Ba¨r et al., 2002). These tactile hallucinations have been shown to correlate with activation of somatosensory brain areas (Ba¨r et al., 2002), and they might be difficult to distinguish from other pain complaints. It is surprising that despite the clinical relevance relatively few studies have addressed the issue of pain perception in schizophrenia (Hall and Stride, 1954; Merskey et al., 1962; Collins and Stone, 1966; Davis et al., 1979; Guieu et al., 1994; Blumensohn et al., 2002) and their relatives (Hooley and Delgado, 2001). Some of them have shown that schizophrenic patients are less sensitive to painful stimuli (Hall and Stride, 1954; Davis et al., 1979; Blumensohn et al., 2002). Hall and Stride, for instance, reported a significantly increased pain threshold in schizophrenic patients. In another study examining pain ratings, a poorer ability to discriminate between noxious and non-noxious electrical stimuli was demonstrated in patients with schizophrenia in comparison to normal controls (Davis et al., 1979). Those results are supported by Blumensohn et al. who found higher pain parameters (sensation threshold, pain threshold and pain tolerance) in schizophrenic patients using current-induced pain (Blumensohn et al., 2002). Some authors have suggested that antipsychotics have analgesic properties and might be responsible for altered pain processing in schizophrenia (Simon, 1976; Kocher, 1981; Fishbain, 1982; Jakubaschk and Boker, 1991; Guieu et al., 1994). However, this hypalgesia in schizophrenia was not unequivocally verified in all studies. Guieu et al. found no difference in nociceptive thresholds between unmedicated schizophrenic patients and healthy controls based on the nociceptive reflex. They concluded that increased pain thresholds in schizophrenia are a reaction of denial rather than binsensibilityQ to pain
and depend on the attitude (Guieu et al., 1994). In addition Dworkin pointed out that research so far provides neither an acceptable description nor a sufficient explanation for altered pain perception in schizophrenia (Dworkin, 1994). The earlier studies are often limited by important methodological flaws, including small sample sizes, lack of careful examination of medication effects, problematic control groups and limitations of the psychophysical methods used in assessing pain sensitivity. We have therefore investigated thresholds of warmth perception (WP) and thermal pain onset (TPO) as well as thermal pain tolerance (TPT) in 23 acutely ill schizophrenic patients. Patients who had not taken any antipsychotic medication for at least 8 weeks were included for the initial investigation. Patients were reinvestigated 3 days after initiation of treatment in order to describe the influence of antipsychotic medication. Results of pain testing were then correlated with epidemiological data and psychopathological scales.
2. Methods 2.1. Subjects Twenty-three patients suffering from paranoid schizophrenia and 23 controls matched in respect to age, gender, handedness and education were investigated. Control persons were recruited from hospital staff. The protocol included tests on each point in time for WP, TPO and TPT. Patients and control subjects with a clinical history of peripheral neuropathies, upper limb trauma, drug intoxication and alcohol dependency were excluded from the study. Paranoid schizophrenia was diagnosed by a staff psychiatrist when symptoms of patients who had been admitted to our inpatient wards fulfilled DSM-IV criteria. Acute symptoms of schizophrenia were assessed based on a semi-structured clinical interview and the Scales for the Assessment of Positive (SAPS) and Negative Symptoms (SANS) (Andreasen et al., 1995). Patients who had not taken antipsychotic treatment for at least 8 weeks were allocated to the first phase of the study (A) and reassessed a second time (B) in a comparable clinical state after receiving neuroleptics 3 days later (see Table 1).
T. Jochum et al. / Psychiatry Research 142 (2006) 151–156
153
Table 1 Clinical and demographic data of participants
Number of participants (male/female) Demographic data Age (years) Education Primary Secondary SAPS/SANS (time category A) SAPS/SANS (time category B) First episode of psychosis Duration of disease in years (min–max) Medication with average dosage (time category B) Atypical antipsychotic drugs Olanzapine (5–10 mg); risperidone (2–4 mg); quetiapine (100–200 mg); amisulpride (400 mg) Haldoperidol (1–2 mg)
Controls with a history of psychiatric disorder including personality disorders or with a history of psychotherapy were excluded from the study. All investigations were performed between 4:00 and 8:00 p.m. Controls were studied at both times in parallel with patients. All participants gave written informed consent to the protocol approved by the Ethics Committee of the Medical Faculty. 2.2. Heat pain measures Heat pain measures were performed as previously published (Ba¨r et al., 2003). Measurements were made in a quiet room that was kept comfortably warm. WP, TPO and TPT were determined by an ascending Method of Limits, using a 9-cm2 contact thermode with a rate of temperature change of 0.5 8C/ s (starting temperature: 32.0 8C; maximum temperature: 53.0 8C). The thermode was attached to the left or right volar wrist. All patients and control subjects were studied on both arms. WP, TPO and TPT were always measured in that order, firstly on one arm. For each variable, three learning trials were performed to allow subjects to adjust to the actual protocol demands, and were not processed in later data analysis. After this, five more tests were performed and these measurements were averaged. To determine WP, subjects received a written instruction: bPress the stop button as soon as the warming of the thermode is perceivedQ. To determine TPO, subjects were asked to read the written instruction: bPress the stop button
Patients with acute schizophrenia
Control subjects
23 (7 / 16)
23 (7 / 16)
34.4 F 2.5 (19–55)
37.8 F 2.2 (22–58)
n =7 n = 16 47.4 F 5.3 / 32.5 F 4.8 36.5 F 5.3 / 29.1 F 4.5 n =7 8.6 F 1.7 (0–29)
n =7 n = 16
n = 18 n = 8; n = 8 n = 1; n = 1 n =5
immediately when thermal perception first becomes painfulQ. Values for TPO below 39 8C were regarded as non-painful, excluded from analysis, and taken to suggest that the participant did not understand task instructions. Two patients were therefore excluded because they indicated heat pain at temperatures below 36 8C which, according to Meh and Denislic, are out of the range of heat–pain thresholds (Meh and Denislic, 1994). For TPT, subjects were instructed to press the stop button when they could not tolerate the temperature any longer. After measuring WP, TPO and TPT for one arm, the whole procedure was repeated for the second arm. The order of the side tested first was counterbalanced and pseudo-randomized across subjects. The first subject was first tested on the right arm, then on the left arm; the second subject first on the left arm, then on the right arm. 2.3. Statistical reporting To compare schizophrenic patients with matched controls, we used a multivariate analysis of variance (MANOVA) as an overall test. Follow-up univariate analyses of variance (ANOVAs) were performed for WP, TPO and TPT with the factors Group, Time (unmedicated vs. medicated) and Side (left or right arm) to assess differences between groups, the effect of medication, the effect of lateralization and the interactions between these factors. Finally post hoc
T. Jochum et al. / Psychiatry Research 142 (2006) 151–156
t-tests were performed to compare thresholds of patients and controls at both time points. Additionally, we correlated heat pain parameters and severity of positive (SAPS) and negative (SANS) symptoms. Pairwise Student’s t-tests were performed to compare SAPS and SANS scores at both time points. Threshold levels of significance were adjusted for multiple comparisons by Bonferroni’s correction.
3. Results 3.1. Multivariate statistic Using multivariate ANOVA to compare schizophrenic patients with matched controls, we found a significant overall main effect for the between-subjects factor Group (Wilks’ Lambda = 0.68; F(2, 43) = 6.35, P = 0.001). There were no overall effects for subjects’ factors within Time, Side or interactions between Group, Time and Side.
A
Warmth perception 38 37 36
temperature [°°C]
154
**
left
right
acute, on medication **
34 33 32 31 30
B
left
right
Thermal pain onset 52 51 50
3.2. Univariate statistics
acute, no medication
acute, on medication
*
*
**
left
right
left
temperature [°C]
48 47 46 45 44 43 42 41 40 39 38
C
temperature [°C]
Fig. 1. A: Comparisons of warmth perception in patients and controls; t-tests revealed that schizophrenic patients perceived warmth significantly later at both assessments (with and without neuroleptic medication) on the right arm and on the left arm in the unmedicated state only. B: t-tests showed significant differences in thresholds of thermal pain onset in patients and controls. Schizophrenic patients indicated pain whilst off medication significantly later than controls. Differences remained on the left arm after introduction of antipsychotic medication. There were no significant differences in the tolerance of thermal pain, shown in C, either before or after the administration of neuroleptics (P b 0.05, **P b 0.01, two-tailed t-test at each time point).
*
35
49
Follow-up univariate ANOVAs revealed a highly significant main effect of Group for warmth perception [ F(1, 44) = 11.42, P = 0.002] and a significant effect for heat pain threshold [ F(1, 44) = 7.33, P = 0.010] (Fig. 1A–B). This means schizophrenic patients indicated perception for warmth later than controls and had a higher threshold for heat pain. Heat pain tolerance was not significantly different between groups (Fig. 1C). There were no significant effects for the Time, Side, Group Side interaction or for the Group Time Side interaction.
acute, no medication
right
Heat pain tolerance 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40
acute, no medication
left
right controls
acute, on medication
left
right
schizophrenic
T. Jochum et al. / Psychiatry Research 142 (2006) 151–156
3.3. Post hoc t-tests of WP, TPO and TPT Levels of significance of the comparison of thresholds of schizophrenic patients and controls are presented in Fig. 1A–C. 3.4. Correlation of psychometric scales with severity of illness We found no significant correlations between SAPS or SANS scores and heat pain parameters for any time point. Comparing both time points using the paired ttest, we found significant differences of the psychometric parameters SAPS ( P b 0.008) and SANS ( P b 0.009) after the introduction of medication (Table 1).
4. Discussion It is surprising that the phenomenon of pain insensitivity in schizophrenia has not attracted more research interest in the past. Our main finding was a significant increase of thresholds in warmth perception (WP) and thermal pain onset (TPO) in acutely ill schizophrenic patients. This corroborates results of some earlier studies of diminished pain perception in schizophrenia (Malmo et al., 1951; Sappington, 1973; Bickerstaff et al., 1988; Jakubaschk and Boker, 1991). It is likely that similar mechanisms cause hypalgesia to laboratory-induced pain and provoke pain insensitivity in emergency cases involving schizophrenic patients (Fishbain, 1982; Bickerstaff et al., 1988, Rosenthal et al., 1990). In addition to earlier studies, our results indicate that altered perception of warmth and heat pain is not specific to the pain system. We suggest rather that it belongs to the impairment in executive functioning of schizophrenic patients (Davis et al., 1979; Nuechterlein et al., 1994; Velligan et al., 2002; Frecska et al., 2004). It has been shown, in particular, that perception, attention, vigilance and the executive use of active working memory are altered in schizophrenic patients (Nuechterlein et al., 1994). We believe that those information-processing abnormalities might have led to group differences of thresholds of WP and TPO as well as to results of TPT testing. The test procedure of WP required a quick response from the participant within 2–4 s, since
155
temperature started at 32 8C and was felt in average at 34 8C by control participants. This was obviously not achieved by our patients. In contrast, the TPT testing required sustained attention. Control subjects felt pain intolerable (TPT test) above 50 8C. This test therefore lasted in average 36 s (rate of temperature change 0.5 8C/s; starting temperature: 32.0 8C). It was obvious during test procedure that most patients had major difficulties in focusing on the test. Therefore, it is not likely that we really obtained pain tolerance. However, this might well correspond to clinical pain conditions such as deep somatic pain, when patients fail to pay attention to a sensory perception. Secondly, we did not observe any effect of antipsychotics on WP, TPO and TPT after treatment was initiated. This indicates that antipsychotics play only a minor role in pain perception abnormalities of schizophrenic patients (Merskey et al., 1962; Haas et al., 1982). Furthermore, it is important to comprehend that the analgesic action of these drugs is less pronounced than suggested before (Hall and Stride, 1954; Simon, 1976; Haas et al., 1982; Jakubaschk and Boker, 1991). On the contrary, univariate F-values imply that the significant effect was somewhat weaker at post-medication (although there was no interaction between Group and Time), indicating that differences between patients and control subjects became less pronounced. In relation to our hypothesis of altered pain perception in schizophrenia, we would like to suggest that antipsychotic medication led to an improvement of executive functioning and might therefore be responsible for smaller differences. This assumption is supported by a significant clinical improvement as demonstrated in psychometric scales (SANS and SAPS) that are known to have good validity and reliability for psychotic, disorganised, and negative symptoms (Andreasen et al., 1995). Several limitations inherent to our study need to be considered when interpreting our results. First of all, we have not determined any cognitive function for our patients and can therefore only speculate about a possible link between impairment of cognitive function and pain processing. Secondly, we reinvestigated patients 3 days after the initiation of treatment. This time interval was chosen to keep the clinical state approximately comparable, since the introduction of treatment and a completely altered clinical state would have made interpretation of results impossible. How-
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ever, a longer steady state of antipsychotics might have different effects on pain perception. Further studies are warranted to investigate the specific influence of antipsychotics on information-processing in relation to pain perception. Various studies have investigated hemispheric dysfunction in schizophrenia (Malaspina et al., 1997; Flor-Henry, 1976). Therefore we have determined pain perception on the right and left arm. In contrast to findings in depressive patients (Ba¨r et al., 2003), we have not found any indication of lateralization of pain perception in schizophrenia. In conclusion, our results indicate that pain and warmth perceptions are altered in schizophrenia, and we suggest that abnormalities of pain perception relate to information-processing abnormalities of the disease.
References Andreasen, N.C., Arndt, S., Miller, D., Flaum, M., Nopoulos, P., 1995. Correlational studies of the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms: an overview and update. Psychopathology 28, 7 – 17. Ba¨r, K.J., Gaser, C., Nenadic, I., Sauer, H., 2002. Transient activation of a somatosensory area in painful hallucinations shown by fMRI. Neuroreport 13, 805 – 808. Ba¨r, K.J., Greiner, W., Letzsch, A., Kobele, R., Sauer, H., 2003. Influence of gender and hemispheric lateralization on heat pain perception in major depression. Journal of Psychiatric Research 37, 345 – 353. Bickerstaff, L.K., Harris, S.C., Leggett, R.S., Cheah, K.C., 1988. Pain insensitivity in schizophrenic patients. A surgical dilemma. Archives of Surgery 123, 49 – 51. Blumensohn, R., Ringler, D., Eli, I., 2002. Pain perception in patients with schizophrenia. Journal of Nervous and Mental Disease 190 (7), 481 – 483. Collins, L.G., Stone, L.A., 1966. Pain sensitivity, age and activity level in chronic schizophrenics and in normals. British Journal of Psychiatry 34, 33 – 35. Davis, G.C., Buchsbaum, M.S., van Kammen, D.P., Bunney, W.E., 1979. Analgesia to pain stimuli in schizophrenics and its reversal by naltrexone. Psychiatry Research 1, 61 – 69. Dworkin, R.H., 1994. Pain insensitivity in schizophrenia: a neglected phenomenon and some implications. Schizophrenia Bulletin 20 (2), 235 – 248. Fishbain, D.A., 1982. Pain insensitivity in psychosis. Annals of Emergency Medicine 11, 630 – 632. Flor-Henry, P., 1976. Lateralized temporal-limbic dysfunction and psychopathology. Annals of the New York Academy of Sciences 280, 777 – 797. Frecska, E., Symer, C., White, K., Piscani, K., Kulcsar, Z., 2004. Perceptional and executive deficits of chronic schizophrenic
patients in attentional and intentional tasks. Psychiatry Research 126 (1), 63 – 75. Guieu, R., Samuelian, J.C., Coulouvrat, H., 1994. Objective evaluation of pain perception in patients with schizophrenia. British Journal of Psychiatry 164, 253 – 255. Haas, S., Emrich, H.M., Beckmann, H., 1982. Analgesic and euphoric effects of high dose diazepam in schizophrenia. Neuropsychobiology 8, 123 – 128. Hall, K.R.L., Stride, E., 1954. The varying response to pain in psychiatric disorders: a study of abnormal psychology. British Journal of Medical Psychology 27, 48 – 60. Huber, G., 1957. Coenaesthetic schizophrenia. Neurologie 25, 491 – 520. Hooley, J.M., Delgado, M.L., 2001. Pain insensitivity in the relatives of schizophrenia patients. Schizophrenia Research 47 (2– 3), 265 – 273. Jakubaschk, J., Boker, W., 1991. Disorders of pain perception in schizophrenia. Schweizer Archiv der Neurologie und Psychiatrie 142, 55 – 76. Kocher, R., 1981. Psychotropic-drugs in the treatment of chronic pain. Schweizerische Medizinische Wochenschrift 111, 1946 – 1954. Malaspina, D., Bruder, G., Dalack, G.W., Storer, S., van Kammen, M., Amador, X., Glassman, A., Gorman, J., 1997. Diminished cardiac vagal tone in schizophrenia: associations to brain laterality and age of onset. Biological Psychiatry 41 (5), 612 – 617. Malmo, R.B., Shagass, C., Smith, A.A., 1951. Responsiveness in chronic schizophrenia. Journal of Personality 163, 359 – 375. Meh, D., Denislic, M., 1994. Quantitative assessment of thermal and pain sensitivity. Journal of the Neurological Sciences 127, 164 – 169. Merskey, H., Gillis, A., Marszalek, K.S., 1962. A clinical investigation of reactions to pain. Journal of Mental Science 12, 347 – 355. Nuechterlein, K.H., Dawson, M.E., Green, M.F., 1994. Informationprocessing abnormalities as neuropsychological vulnerability indicators for schizophrenia. Acta Psychiatrica Scandinavica Supplement 384, 71 – 79. Rosenthal, S.H., Porter, K.A., Coffey, B., 1990. Pain insensitivity in schizophrenia. Case report and review of the literature. General Hospital Psychiatry 12, 319 – 322. Sappington, J., 1973. Thresholds of shock-induced discomfort in process and reactive schizophrenics. Perceptual and Motor Skills 37, 489 – 490. Simon, E.J., 1976. Opiate receptors. Neurochemical Research 1, 3 – 28. Velligan, D.I., Ritch, J.L., Sui, D., DiCocco, M., Huntzinger, C.D., 2002. Frontal Systems Behavior Scale in schizophrenia: relationships with psychiatric symptomatology, cognition and adaptive function. Psychiatry Research 113 (3), 227 – 236.
Further reading Ba¨r, K.J., Jochum, T., Hager, F., Meissner, W., Sauer, H., 2005. Painful hallucinations and somatic delusions in a patient with the possible diagnosis of neuroborreliosis. Clinical Journal of Pain 21, 362 – 363.
Influence of antipsychotic medication on pain perception in schizophrenia Thomas Jochum, Andrea Letzsch, Wolf Greiner, Gerd Wagner, Heinrich Sauer, Karl-Ju¨rgen Ba¨r * Department of Psychiatry, Friedrich-Schiller-University of Jena, Philosophenweg 3, 07743 Jena, Germany Received 20 October 2004; accepted 17 September 2005
Abstract A number of clinical observations indicate that pain processing might be disturbed in psychotic disorders such as schizophrenia. Only a few studies have investigated pain perception in schizophrenia. The main objective of this study was the investigation of thresholds of warmth perception (WP), thermal pain onset (TPO) and thermal pain tolerance (TPT) in acute schizophrenic patients and the influence of antipsychotic medication on the patients’ responses. We investigated 23 schizophrenic subjects who had been not received antipsychotic treatment for 8 weeks, and we then reassessed them 3 days later after the introduction of neuroleptics. Acute symptoms of schizophrenia were measured using the Scales for the Assessment of Positive and Negative Symptoms. Thresholds were determined by a contact thermode on both volar wrists. Schizophrenic patients showed significantly increased thresholds of WP and TPO relative to healthy controls. Antipsychotics did not alter pain thresholds. We found no correlation between pain perception and psychometric scales. Our findings demonstrate altered warmth and heat pain perception in acute schizophrenia. We believe that our findings can be attributed to information-processing abnormalities of the disorder and that they are not specific to pain processing, per se, since both WP and TPO were significantly different. Future studies should evaluate attentional deficits in schizophrenia in relation to pain perception. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Cognition; Neuroleptic treatment; Pain; Perception; Schizophrenia; Threshold
1. Introduction
* Corresponding author. Tel.: +49 3641 935282; fax: +49 3641 936217. E-mail address: [email protected] (K.-J. Ba¨r).
A number of clinical observations indicate that pain processing is disturbed in psychotic disorders such as schizophrenia. For example, schizophrenic patients may suffer from peritonitis, severe burns, fractures or myocardial infarction and show only minor indications of pain (Bickerstaff et al., 1988;
0165-1781/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2005.09.004
152
T. Jochum et al. / Psychiatry Research 142 (2006) 151–156
Rosenthal et al., 1990; Jakubaschk and Boker, 1991). It is noteworthy that this clinical phenomenon of pain insensitivity in schizophrenia has been particularly described by surgeons and anesthesiologists since they had to treat life-threatening sequels. Moreover schizophrenic patients are very rarely found in populations of chronic pain patients and are seldom known to suffer from post-puncture headache or migraine (Dworkin, 1994). Conversely, schizophrenic patients can present with bizarre sensory complaints (Huber, 1957) such as bpins and needlesQ in a sub-syndrome of schizophrenia called coenesthesia (Ba¨r et al., 2002). These tactile hallucinations have been shown to correlate with activation of somatosensory brain areas (Ba¨r et al., 2002), and they might be difficult to distinguish from other pain complaints. It is surprising that despite the clinical relevance relatively few studies have addressed the issue of pain perception in schizophrenia (Hall and Stride, 1954; Merskey et al., 1962; Collins and Stone, 1966; Davis et al., 1979; Guieu et al., 1994; Blumensohn et al., 2002) and their relatives (Hooley and Delgado, 2001). Some of them have shown that schizophrenic patients are less sensitive to painful stimuli (Hall and Stride, 1954; Davis et al., 1979; Blumensohn et al., 2002). Hall and Stride, for instance, reported a significantly increased pain threshold in schizophrenic patients. In another study examining pain ratings, a poorer ability to discriminate between noxious and non-noxious electrical stimuli was demonstrated in patients with schizophrenia in comparison to normal controls (Davis et al., 1979). Those results are supported by Blumensohn et al. who found higher pain parameters (sensation threshold, pain threshold and pain tolerance) in schizophrenic patients using current-induced pain (Blumensohn et al., 2002). Some authors have suggested that antipsychotics have analgesic properties and might be responsible for altered pain processing in schizophrenia (Simon, 1976; Kocher, 1981; Fishbain, 1982; Jakubaschk and Boker, 1991; Guieu et al., 1994). However, this hypalgesia in schizophrenia was not unequivocally verified in all studies. Guieu et al. found no difference in nociceptive thresholds between unmedicated schizophrenic patients and healthy controls based on the nociceptive reflex. They concluded that increased pain thresholds in schizophrenia are a reaction of denial rather than binsensibilityQ to pain
and depend on the attitude (Guieu et al., 1994). In addition Dworkin pointed out that research so far provides neither an acceptable description nor a sufficient explanation for altered pain perception in schizophrenia (Dworkin, 1994). The earlier studies are often limited by important methodological flaws, including small sample sizes, lack of careful examination of medication effects, problematic control groups and limitations of the psychophysical methods used in assessing pain sensitivity. We have therefore investigated thresholds of warmth perception (WP) and thermal pain onset (TPO) as well as thermal pain tolerance (TPT) in 23 acutely ill schizophrenic patients. Patients who had not taken any antipsychotic medication for at least 8 weeks were included for the initial investigation. Patients were reinvestigated 3 days after initiation of treatment in order to describe the influence of antipsychotic medication. Results of pain testing were then correlated with epidemiological data and psychopathological scales.
2. Methods 2.1. Subjects Twenty-three patients suffering from paranoid schizophrenia and 23 controls matched in respect to age, gender, handedness and education were investigated. Control persons were recruited from hospital staff. The protocol included tests on each point in time for WP, TPO and TPT. Patients and control subjects with a clinical history of peripheral neuropathies, upper limb trauma, drug intoxication and alcohol dependency were excluded from the study. Paranoid schizophrenia was diagnosed by a staff psychiatrist when symptoms of patients who had been admitted to our inpatient wards fulfilled DSM-IV criteria. Acute symptoms of schizophrenia were assessed based on a semi-structured clinical interview and the Scales for the Assessment of Positive (SAPS) and Negative Symptoms (SANS) (Andreasen et al., 1995). Patients who had not taken antipsychotic treatment for at least 8 weeks were allocated to the first phase of the study (A) and reassessed a second time (B) in a comparable clinical state after receiving neuroleptics 3 days later (see Table 1).
T. Jochum et al. / Psychiatry Research 142 (2006) 151–156
153
Table 1 Clinical and demographic data of participants
Number of participants (male/female) Demographic data Age (years) Education Primary Secondary SAPS/SANS (time category A) SAPS/SANS (time category B) First episode of psychosis Duration of disease in years (min–max) Medication with average dosage (time category B) Atypical antipsychotic drugs Olanzapine (5–10 mg); risperidone (2–4 mg); quetiapine (100–200 mg); amisulpride (400 mg) Haldoperidol (1–2 mg)
Controls with a history of psychiatric disorder including personality disorders or with a history of psychotherapy were excluded from the study. All investigations were performed between 4:00 and 8:00 p.m. Controls were studied at both times in parallel with patients. All participants gave written informed consent to the protocol approved by the Ethics Committee of the Medical Faculty. 2.2. Heat pain measures Heat pain measures were performed as previously published (Ba¨r et al., 2003). Measurements were made in a quiet room that was kept comfortably warm. WP, TPO and TPT were determined by an ascending Method of Limits, using a 9-cm2 contact thermode with a rate of temperature change of 0.5 8C/ s (starting temperature: 32.0 8C; maximum temperature: 53.0 8C). The thermode was attached to the left or right volar wrist. All patients and control subjects were studied on both arms. WP, TPO and TPT were always measured in that order, firstly on one arm. For each variable, three learning trials were performed to allow subjects to adjust to the actual protocol demands, and were not processed in later data analysis. After this, five more tests were performed and these measurements were averaged. To determine WP, subjects received a written instruction: bPress the stop button as soon as the warming of the thermode is perceivedQ. To determine TPO, subjects were asked to read the written instruction: bPress the stop button
Patients with acute schizophrenia
Control subjects
23 (7 / 16)
23 (7 / 16)
34.4 F 2.5 (19–55)
37.8 F 2.2 (22–58)
n =7 n = 16 47.4 F 5.3 / 32.5 F 4.8 36.5 F 5.3 / 29.1 F 4.5 n =7 8.6 F 1.7 (0–29)
n =7 n = 16
n = 18 n = 8; n = 8 n = 1; n = 1 n =5
immediately when thermal perception first becomes painfulQ. Values for TPO below 39 8C were regarded as non-painful, excluded from analysis, and taken to suggest that the participant did not understand task instructions. Two patients were therefore excluded because they indicated heat pain at temperatures below 36 8C which, according to Meh and Denislic, are out of the range of heat–pain thresholds (Meh and Denislic, 1994). For TPT, subjects were instructed to press the stop button when they could not tolerate the temperature any longer. After measuring WP, TPO and TPT for one arm, the whole procedure was repeated for the second arm. The order of the side tested first was counterbalanced and pseudo-randomized across subjects. The first subject was first tested on the right arm, then on the left arm; the second subject first on the left arm, then on the right arm. 2.3. Statistical reporting To compare schizophrenic patients with matched controls, we used a multivariate analysis of variance (MANOVA) as an overall test. Follow-up univariate analyses of variance (ANOVAs) were performed for WP, TPO and TPT with the factors Group, Time (unmedicated vs. medicated) and Side (left or right arm) to assess differences between groups, the effect of medication, the effect of lateralization and the interactions between these factors. Finally post hoc
T. Jochum et al. / Psychiatry Research 142 (2006) 151–156
t-tests were performed to compare thresholds of patients and controls at both time points. Additionally, we correlated heat pain parameters and severity of positive (SAPS) and negative (SANS) symptoms. Pairwise Student’s t-tests were performed to compare SAPS and SANS scores at both time points. Threshold levels of significance were adjusted for multiple comparisons by Bonferroni’s correction.
3. Results 3.1. Multivariate statistic Using multivariate ANOVA to compare schizophrenic patients with matched controls, we found a significant overall main effect for the between-subjects factor Group (Wilks’ Lambda = 0.68; F(2, 43) = 6.35, P = 0.001). There were no overall effects for subjects’ factors within Time, Side or interactions between Group, Time and Side.
A
Warmth perception 38 37 36
temperature [°°C]
154
**
left
right
acute, on medication **
34 33 32 31 30
B
left
right
Thermal pain onset 52 51 50
3.2. Univariate statistics
acute, no medication
acute, on medication
*
*
**
left
right
left
temperature [°C]
48 47 46 45 44 43 42 41 40 39 38
C
temperature [°C]
Fig. 1. A: Comparisons of warmth perception in patients and controls; t-tests revealed that schizophrenic patients perceived warmth significantly later at both assessments (with and without neuroleptic medication) on the right arm and on the left arm in the unmedicated state only. B: t-tests showed significant differences in thresholds of thermal pain onset in patients and controls. Schizophrenic patients indicated pain whilst off medication significantly later than controls. Differences remained on the left arm after introduction of antipsychotic medication. There were no significant differences in the tolerance of thermal pain, shown in C, either before or after the administration of neuroleptics (P b 0.05, **P b 0.01, two-tailed t-test at each time point).
*
35
49
Follow-up univariate ANOVAs revealed a highly significant main effect of Group for warmth perception [ F(1, 44) = 11.42, P = 0.002] and a significant effect for heat pain threshold [ F(1, 44) = 7.33, P = 0.010] (Fig. 1A–B). This means schizophrenic patients indicated perception for warmth later than controls and had a higher threshold for heat pain. Heat pain tolerance was not significantly different between groups (Fig. 1C). There were no significant effects for the Time, Side, Group Side interaction or for the Group Time Side interaction.
acute, no medication
right
Heat pain tolerance 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40
acute, no medication
left
right controls
acute, on medication
left
right
schizophrenic
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3.3. Post hoc t-tests of WP, TPO and TPT Levels of significance of the comparison of thresholds of schizophrenic patients and controls are presented in Fig. 1A–C. 3.4. Correlation of psychometric scales with severity of illness We found no significant correlations between SAPS or SANS scores and heat pain parameters for any time point. Comparing both time points using the paired ttest, we found significant differences of the psychometric parameters SAPS ( P b 0.008) and SANS ( P b 0.009) after the introduction of medication (Table 1).
4. Discussion It is surprising that the phenomenon of pain insensitivity in schizophrenia has not attracted more research interest in the past. Our main finding was a significant increase of thresholds in warmth perception (WP) and thermal pain onset (TPO) in acutely ill schizophrenic patients. This corroborates results of some earlier studies of diminished pain perception in schizophrenia (Malmo et al., 1951; Sappington, 1973; Bickerstaff et al., 1988; Jakubaschk and Boker, 1991). It is likely that similar mechanisms cause hypalgesia to laboratory-induced pain and provoke pain insensitivity in emergency cases involving schizophrenic patients (Fishbain, 1982; Bickerstaff et al., 1988, Rosenthal et al., 1990). In addition to earlier studies, our results indicate that altered perception of warmth and heat pain is not specific to the pain system. We suggest rather that it belongs to the impairment in executive functioning of schizophrenic patients (Davis et al., 1979; Nuechterlein et al., 1994; Velligan et al., 2002; Frecska et al., 2004). It has been shown, in particular, that perception, attention, vigilance and the executive use of active working memory are altered in schizophrenic patients (Nuechterlein et al., 1994). We believe that those information-processing abnormalities might have led to group differences of thresholds of WP and TPO as well as to results of TPT testing. The test procedure of WP required a quick response from the participant within 2–4 s, since
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temperature started at 32 8C and was felt in average at 34 8C by control participants. This was obviously not achieved by our patients. In contrast, the TPT testing required sustained attention. Control subjects felt pain intolerable (TPT test) above 50 8C. This test therefore lasted in average 36 s (rate of temperature change 0.5 8C/s; starting temperature: 32.0 8C). It was obvious during test procedure that most patients had major difficulties in focusing on the test. Therefore, it is not likely that we really obtained pain tolerance. However, this might well correspond to clinical pain conditions such as deep somatic pain, when patients fail to pay attention to a sensory perception. Secondly, we did not observe any effect of antipsychotics on WP, TPO and TPT after treatment was initiated. This indicates that antipsychotics play only a minor role in pain perception abnormalities of schizophrenic patients (Merskey et al., 1962; Haas et al., 1982). Furthermore, it is important to comprehend that the analgesic action of these drugs is less pronounced than suggested before (Hall and Stride, 1954; Simon, 1976; Haas et al., 1982; Jakubaschk and Boker, 1991). On the contrary, univariate F-values imply that the significant effect was somewhat weaker at post-medication (although there was no interaction between Group and Time), indicating that differences between patients and control subjects became less pronounced. In relation to our hypothesis of altered pain perception in schizophrenia, we would like to suggest that antipsychotic medication led to an improvement of executive functioning and might therefore be responsible for smaller differences. This assumption is supported by a significant clinical improvement as demonstrated in psychometric scales (SANS and SAPS) that are known to have good validity and reliability for psychotic, disorganised, and negative symptoms (Andreasen et al., 1995). Several limitations inherent to our study need to be considered when interpreting our results. First of all, we have not determined any cognitive function for our patients and can therefore only speculate about a possible link between impairment of cognitive function and pain processing. Secondly, we reinvestigated patients 3 days after the initiation of treatment. This time interval was chosen to keep the clinical state approximately comparable, since the introduction of treatment and a completely altered clinical state would have made interpretation of results impossible. How-
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ever, a longer steady state of antipsychotics might have different effects on pain perception. Further studies are warranted to investigate the specific influence of antipsychotics on information-processing in relation to pain perception. Various studies have investigated hemispheric dysfunction in schizophrenia (Malaspina et al., 1997; Flor-Henry, 1976). Therefore we have determined pain perception on the right and left arm. In contrast to findings in depressive patients (Ba¨r et al., 2003), we have not found any indication of lateralization of pain perception in schizophrenia. In conclusion, our results indicate that pain and warmth perceptions are altered in schizophrenia, and we suggest that abnormalities of pain perception relate to information-processing abnormalities of the disease.
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Further reading Ba¨r, K.J., Jochum, T., Hager, F., Meissner, W., Sauer, H., 2005. Painful hallucinations and somatic delusions in a patient with the possible diagnosis of neuroborreliosis. Clinical Journal of Pain 21, 362 – 363.