Journal of Behavioral Medicine, Vol. 30, No. 1, February 2007 ( C 2006) DOI: 10.

1007/s10865-006-9084-1

Effects of Opioid Blockade with Naltrexone and Distraction on Cold and Ischemic Pain in Hypertension
Christopher Ring,1,5 Christopher R. France,2 Mustafa alAbsi,3 Louise Beesley,4 Louisa Edwards,1 David McIntyre,1 Douglas Carroll,1 and Una Martin4
Accepted for publication: October 16, 2006 Published online: January 5, 2007

Essential hypertension is characterised by reduced pain sensitivity. Hypertensive hypoalgesia has been attributed to elevated endogenous opioids and/or increased activation of descending pain modulation systems. A double-blind placebo-controlled design compared the effects of naltrexone and placebo on cold and ischemic pain in unmedicated newly-diagnosed patients with essential hypertension. Patients performed a cold pressor task while resting and while performing a distracting secondary task. They also performed a forearm ischemia task while resting. Although the cold pressor and ischemia tasks elicited signicant increases in pain and blood pressure, pain ratings and pressor responses did not differ between naltrexone and placebo. Cold pain was reduced by distraction compared to rest. The nding that opioid blockade with naltrexone did not moderate the pain and pressor responses to cold and ischemia suggests that pain and associated blood pressure responses are not modulated by opioids in hypertension. The nding that the distracting secondary task successfully reduced pain ratings suggests normal supraspinal pain modulation in essential hypertension.
KEY WORDS: distraction; endogenous opioids; hypertension; hypoalgesia; naltrexone; pain.

INTRODUCTION That individuals with hypertension experience less pain during noxious stimulation compared to individuals with blood pressure in the normal range is well documented (Ghione, 1996). However, the mechanism underlying hypertensive hypoalgesia remains to be established. In an extension of McCubbins (1991, 1993) model of central opioid insensitivity in the etiology of hypertension, France and Ditto (1996) proposed a model in which pain insensitivity in hypertension could be explained by a
1 International

Centre for Health and Exercise Research, University of Birmingham, Birmingham, B15 2TT, UK. 2 Department of Psychology, Ohio University, Athens, OH 45701, USA. 3 Department of Behavioral Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA. 4 Wellcome Trust Clinical Research Facility, School of Medicine, University of Birmingham, Birmingham B15 2TT, UK. 5 To whom correspondence should be addressed e-mail: c.m.ring@bham.ac.uk.

number of mechanisms, including opioid dysfunction and/or and enhanced activation of descending pain modulation systems. The phenomenon of hypertensive hypoalgesia was rst described in laboratory animals; the involvement of endogenous opioids was clearly established by evidence that differences in nociceptive responding between hypertensive and normotensive rodents was abolished following administration of opioid antagonists (Maixner et al., 1982; Naranjo and Fuentes, 1985; Saavedra, 1981; Sitsen and de Jong, 1983, 1984; Zamir and Segal, 1979; Zamir, Simantov, and Segal 1980). A key study observed that hypertensive hypoalgesia was not abolished by a peripherally acting opioid antagonist, suggesting a role for opioid receptors within the brain (Sitsen and deJong, 1984). In human studies, the evidence for an opioid mechanism is mixed. Hypertension appears to be characterised by greater levels of beta-endorphins in the peripheral circulation (Farsang et al., 1983; Guasti et al., 1996; Hughes et al., 1991; McNeilly and Zeichner, 1989; Sheps et al., 1992) and a couple of studies have argued 59
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60 that the administration of opioid antagonists moderate the pain-blood pressure relationship in young normotensive adults (McCubbin and Bruehl, 1994; McCubbin et al., 2006). In contrast, other pharmacological blockade studies have failed to support the hypothesis that endogenous opioids are responsible for hypertensive hypoalgesia (Bruehl et al., 2002; France et al., 2005; Schobel et al., 1998). It should be noted that although Schobel and colleagues found that the association between blood pressure and pain ratings to noxious mechanical stimulation was not altered by opioid blockade with naloxone, they did nd that naloxone led to higher pain ratings in normotensive men but not borderline hypertensive men. No study to date has examined the effects of opioid blockade on pain in patients with established hypertension. It has also been suggested that hypertensive hypoalgesia may be related to complex interactions between cardiovascular and pain regulatory systems (e.g., Randich and Maixner, 1984; Zamir and Maixner, 1986; Ghione, 1996). Consistent with this notion, France and colleagues (France and Ditto, 1996; France, 1999) proposed that hypoalgesia may be related to enhanced activation of descending pain inhibitory pathways due to the failure of endogenous opioids to provide normal inhibitory feedback to the paraventricular nucleus of the hypothalamus. The hypothalamus is part of a central autonomic network that is responsible for integrating autonomic, neuroendocrine, and behavioral responses to stress (Benarroch, 1993), and this reciprocally-interconnected network includes areas of the forebrain (insular and medial prefrontal cortices, amygdala, hypothalamus), midbrain (periaqueductal gray, pons), and brain stem (nucleus of the solitary tract, ventrolateral medulla). Within this network, the paraventricular nucleus of the hypothalamus serves the crucial function of integrating responses to both painful and non-painful stressors through its innervations of autonomic relay centers, production of corticotrophin releasing factor, and neuronal projections to various areas of the central nervous system involved in pain modulation (Benarroch, 1993; Cechetto and Saper, 1988; Sawchenko and Swanson, 1982; Swanson and Kuypers, 1980). Given the intricate relationship between cardiovascular and pain regulatory systems, it is conceivable that attenuation of normal inhibitory opioid input to the paraventricular nucleus may lead to greater activation of pain inhibitory pathways. Based upon converging neuroanatomical and neuroimaging evidence that cognitive distraction may re-

Ring et al. duce pain by modulating activity in central pain processing networks (Petrovic et al., 2000; Tracey et al., 2002), examination of the effect of distraction on pain perception may provide a preliminary, non-invasive method of examining the integrity of central pain modulation networks. The current study used a double-blind, placebocontrolled design to examine the effects of the opioid antagonist, naltrexone, on pain. In the naltrexone and placebo sessions, pain ratings were determined for cold and ischemic pain tasks. In contrast to most previous pharmacological blockade studies that have investigated the effects of opioid antagonists on pain in individuals with normal or high-normal blood pressure, the current study examined middle-aged patients newly-diagnosed with established high blood pressure who were recruited and tested prior to the start of their anti-hypertensive treatment. The tasks used in the current study assessed prolonged cold and ischemic pain; they were expected to primarily activate C pain bres and induce opioid release (Rosa et al., 1988). To explore the role of pain modulation systems in hypertension, patients performed the cold pressor task while resting and while their attention was distracted from the noxious stimulation by a number repetition and odd-ball digit counting task. METHODS Participants Twenty-four adults were recruited to participate in this double-blind placebo-controlled study. Six participants did not complete all conditions. Thus, the effective sample comprised 18 newly diagnosed and unmedicated hypertensive adults (10 men, 8 women) with a mean age of 44.1 (SD = 11.1) years, mean height of 1.71 (SD = 0.10) m, mean weight of 81.3 (SD = 20.0) kg, and mean body mass index of 27.7 (SD = 5.9) kg/m2 . The study was approved by the local ethics committee and volunteers gave written consent prior to participation. Screening Exclusion Criteria In an initial screening session, each participants medical status and eligibility were determined. The following exclusion criteria were applied: current use of medication, diabetes mellitus, cerebrovascular disease, angina, myocardial infarction, peripheral

Pain in Hypertension vascular disease, neurological disease, chronic liver disease, alcohol intake >28 units (1 unit = 284 ml of beer, 125 ml of wine, or 25 ml of spirits) of alcohol per week in men, >21 units of alcohol per week in women, major psychiatric disorder, secondary hypertension including chronic renal failure, renal artery stenosis, Conns syndrome, or phaeochromocytoma. Blood Pressure Status British Hypertension Society guidelines were used to establish blood pressure status (Ramsay et al., 1999). Each participants blood pressure was measured for 24 h using an ambulatory blood pressure monitor (ABPM) (SpaceLabs Medical, Model 90207). Patients with a systolic blood pressure 160 mmHg or a diastolic blood pressure of 100 mmHg at referral, and conrmed at clinic and on ABPM (mean daytime pressure) were diagnosed as hypertensive; 67% of patients met these criteria. Patients with a systolic blood pressure of 140159 mmHg and/or a diastolic blood pressure of 9099 mmHg at referral, clinic, and on ABPM, were diagnosed as hypertensive if their 10 year coronary heart disease risk was 15% and/or there was evidence of left ventricular hypertrophy on a 12 lead electrocardiograph or echocardiograph, or there was other evidence of end organ damage. The cardiovascular risk prole was calculated using the Joint British Societies Cardiac Risk Assessor computer program (Wood et al., 1998). Blood was sampled to determine renal function, potassium, glucose, cholesterol, high-density lipoprotein, and triglycerides. Urinalysis was also performed. If clinically indicated, patients were screened for evidence of secondary hypertension with renal ultrasound, Doppler imaging of the renal arteries followed by magnetic resonance angiography where indicated, 24 h urinary collection for catecholamines (in triplicate) and renin and aldosterone levels. Physiological Measurements Laboratory systolic blood pressure (mmHg), diastolic blood pressure (mmHg), and heart rate (bpm) were obtained using an oscillometric sphygmomanometer (Omron, 705CP, Omron Health Care Ltd) that has been validated by the European Society of Hypertension (OBrien et al., 2001) with an appropriately sized brachial cuff attached to the participants upper left arm. All blood pressure monitors

61 were regularly calibrated, serviced, and, if necessary, repaired. Procedure The study employed a double-blind placebocontrolled design in which participants completed two three-hour morning sessions, separated by at least 48 h. They were instructed to refrain from caffeine, alcohol, and vigorous exercise for 2 h, and analgesic medication for 24 h prior to testing. At the start of each session, participants sat and relaxed during an initial formal rest period (10 min) while their blood pressure was measured at 0, 270 and 540 s (First Baseline). The investigator then administered a tablet to the participant, which contained either a 50 mg dose of naltrexone or placebo. The order of tablet administration was counterbalanced across participants; in the effective sample, 10 patients received naltrexone in their rst session and eight patients in their second session. The participant was asked to relax for 1 hour to allow for the drug to reach peak circulating levels (Gonzalez and Brogden, 1988). They then completed a second formal rest period (10 min) while their blood pressure was measured at 0, 270 and 540 s (Second Baseline). Sensitivity to cold (cold pain task) and ischemia (ischemic pain task) were then determined: pain ratings were obtained during and immediately after the tasks. A blood pressure measurement was initiated at the start of the rst and second minutes of each cold pressor task and at the start of the rst, third and fth minutes of the forearm ischemia task. At the end of each session, participants sat and relaxed during a nal formal rest period (10 min) while their blood pressure was measured at 0, 270 and 540 s (Recovery). Cold Pain Task Cold sensitivity was assessed during three conditions: quiet sitting (First Rest), distracting number repetition and counting (Distraction), and quiet sitting (Second Rest). Participants were instructed to place their hand up to the wristfold in 4 degree Celsius water for 2 min. They were asked to rate the intensity of the sensation every 30 s using a 0100 rating scale with anchors of no sensation (0), uncomfortable (25), just noticeable pain (50), very painful (75), and maximum tolerable pain (100). If participants removed their hand before the 2 min was up, the tolerance time was recorded, and a rating of 100 was assigned for the remainder of the

62 task. Such premature hand removal occurred for ve or six individuals in all three conditions during each session. In the distraction condition, participants listened to an audio taped presentation of a series of single-digit integers (numbers ranging from 1 to 9) delivered at 34 second intervals. They were asked to repeat each number out loud, and to privately keep count of the occurrence of one number (e.g., 9s). This task was designed to be simple but engaging. A simpler version of this secondary task used in a previous pain study was judged to be distracting and tended to reduce pain compared to rest (Edwards et al., in press). At the end of each task, participants completed a short-form McGill Pain Questionnaire (Melzack, 1987) to indicate retrospectively the pain associated with the cold exposure. Participants rated 11 sensory and four affective descriptors on an intensity scale of 0 (none), 1 (mild), 2 (moderate), and 3 (severe), that were summed to yield the sensory, affective and total pain rating indices. A scale, with anchors of 0 (no pain) and 100 (worst possible pain), was used to indicate an overall pain rating. They also rated their present pain intensity on a scale of 0 (no pain), 1 (mild), 2 (discomforting), 3 (distressing), 4 (horrible), and 5 (excruciating). Each assessment was followed by a 5 minute rest. Ischemic Pain Task Using a hand dynamometer (Lafayette) participants performed rhythmic forearm muscle contractions (contract for two seconds, relax for two seconds) at 50% of pre-determined maximum (M = 32, SD = 9 N) for two minutes. In the last 15 s a brachial cuff was inated to 220 mmHg to occlude blood ow. They then sat quietly for ve minutes with their arm resting horizontally. During this time they provided an intensity rating every 30 s using the rating scale described above. If participants terminated the task before the full 5 minutes was up, which happened with ve participants during the naltrexone session and six during the placebo session, the tolerance time was recorded and a rating of 100 was assigned for the remainder of the task. At the end of the task they completed a short-form McGill Pain Questionnaire. Data Reduction and Statistical Analysis The blood pressure recordings were averaged to provide measures of resting systolic blood pressure and diastolic blood pressure (First Baseline, Second Baseline, Recovery) and measures of task-induced

Ring et al. blood systolic and diastolic pressures (Cold Pressor First Rest, Cold Pressor Distraction, Cold Pressor Second Rest, Forearm Ischemia). The corresponding heart rates were also computed. Statistical analyses were performed using SPSS for Windows 14.0 (SPSS Inc., Chicago, IL, USA). A series of repeated measures multivariate analyses of variance (MANOVAs) were performed on the task-related pain and associated cardiovascular data, with sex as a betweensubjects factor and drug, condition, and time as within-subjects factors. Signicant effects were interrogated using planned comparisons. Eta-squared (2 ), a measure of effect size, is reported. A probability level of less than .05 was taken as signicant. RESULTS Blood Pressure Status The average clinic, ambulatory and initial baseline laboratory blood pressures presented in Table I conrm the blood pressure status of the hypertensive patients. Cold Pain Pain ratings reported every 30 s during the cold pressor task are shown in Fig. 1. A 2 Sex (male, female) 2 Drug (naltrexone, placebo) 3 Condition (rst rest, distraction, second rest) 4 Time (30, 60, 90, 120 s) MANOVA on the pain ratings yielded main effects for condition, F(2, 15) = 10.12, p = .002, 2 = .576, (quadratic term: F(1,16) = 15.51, p = .001; less during distraction than rst rest), and time, F(3, 14) = 31.12, p = .0001, 2 = .870, (cubic term: F(1,16) = 6.64, p = .03; monotonic increase).
Table I. Mean (SD) Blood Pressures of the Hypertensive Patients Variable Clinic Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Ambulatory (day) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Ambulatory (Night) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Laboratory (First Baseline) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (bpm) 162.2 (15.6) 100.9 (13.0) 149.6 (9.5) 98.4 (8.5) 128.6 (15.1) 79.6 (10.0) 155.7 (12.6) 97.1 (8.5) 75.3 (7.9)

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Fig. 2. Mean (SE) pain ratings during the ischemia task during opioid blockade with naltrexone and placebo.

Fig. 1. Mean (SE) pain ratings during the cold pressor under resting and distracting conditions during opioid blockade with naltrexone and placebo.

In addition, the condition by time interaction was signicant, F(6, 11) = 4.59, p = .01, 2 = .740, (quadratic by linear term: F(1, 16) = 5.57, p = .03, 2 = .112). No drug or sex effects were found. The retrospective McGill Pain Questionnaire scores conrmed that cold pressor-induced pain was reduced by distraction but was not affected by opioid blockade (see Table II). Specically, a series of 2 Sex 2 Drug 3 Condition MANOVAs indicated condition main effects for the total pain rating index, F(2, 15) = 7.93, p = .004, 2 = .514, (quadratic term: F(1,16) = 11.62, p = .04; pain lower during distraction than both rests), sensory pain rating index, F(2, 15) = 9.51, p = .002, 2 = .559, (quadratic term: F(1,16) = 16.43, p = .001; pain lower during distraction than both rests), overall pain rating, F(2, 15) = 5.75, p = .01, 2 = .434, (quadratic term: F(1,16) = 7.50, p = .02; pain lower during distraction than the rst rest), and present pain intensity, F(2, 15) = 4.97, p = .02, 2 = .399, (quadratic term: F(1,16) = 10.59, p = .005; pain lower during distraction than rst rest), of the McGill Pain Questionnaire. However, none of the drug or sex effects were signicant.

270, 300 s) MANOVA on the pain ratings yielded a time effect, F(9, 8) = 13.42, p = .001, 2 = .938, (cubic term: F(1,16) = 4.59, p = .05), but no drug or sex effects. Separate 2 Sex 2 Drug ANOVAs were performed on the short-form McGill Pain Questionnaire scores associated with the forearm ischemia task. These analyses revealed no signicant main effects for drug (see Table III). Sex main effects emerged for the overall pain rating, F(1, 16) = 6.95, p = .02, 2 = .303, and present pain intensity, F(1, 16) = 8.62, p = .01, 2 = .350; men reported less ischemic pain than women. In addition, sex by drug interaction effects were found for the total pain rating index, F(1, 16) = 4.54, p = .05, 2 = .221, sensory pain rating index, F(1, 16) = 4.60, p = .05, 2 = .223, and present pain intensity, F(1, 16) = 6.77, p = .02, 2 = .297. As can be seen in Table IV, mens tendency to report less pain than women during placebo was absent during opioid blockade with naltrexone.

Blood Pressure and Heart Rate The resting and task-induced cardiovascular responses during placebo and naltrexone are shown in Fig. 3. Separate 2 Sex 2 Drug 7 Condition (rst baseline, second baseline, cold pressor rst rest, cold pressor distraction, cold pressor second rest, ischemia, recovery) conrmed signicant condition effects for both systolic, F(6, 11) = 20.01, p = .001, 2 = .916, and diastolic, F(6, 11) = 16.29, p = .001, 2 = .899, blood pressures: the tasks elicited signicant pressor responses. A

Ischemic Pain Pain ratings reported every 30 s during the ischemic task are shown in Fig. 2. A 2 Sex 2 Drug 10 Time (30, 60, 90, 120, 150, 180, 210, 240,

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Table II. Mean (SD) Short-Form McGill Pain Questionnaire Data During Opioid Blockade with Naltrexone and Placebo During Rest and Distraction Conditions of the Cold Pressor Task as well as the Statistical Signicance Level of the Drug, Condition, and Drug by Condition Effects Naltrexone Placebo

Variable 11.3 (8.2) 8.6 (5.8) 2.7 (3.1) 78 (20) 2.8 (0.9) 9.7 (9.1) 7.7 (6.4) 2.0 (3.5) 72 (27) 2.4 (1.0) 11.0 (8.2) 8.8 (6.5) 2.2 (3.0) 74 (26) 2.7 (1.1) 8.9 (5.9) 7.4 (5.2) 1.5 (1.7) 76 (20) 2.9 (1.0) 7.7 (5.7) 6.6 (5.0) 1.1 (1.5) 67 (25) 2.5 (1.0) 9.6 (7.6) 8.3 (6.9) 1.3 (1.5) 68 (28) 2.6 (1.2)

First rest Distraction Distraction

Second rest

First rest

Second rest

Drug effect Condition effect Drug by condition effect p p p .13 .28 .14 .35 .87 .004 .002 .26 .01 .02 .81 .92 .49 .62 .86

Total pain rating index (045) Sensory pain rating index (033) Affective pain rating index (012) Overall pain rating (0100) Present pain intensity (05)

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Pain in Hypertension
Table III. Mean (SD) Short-Form McGill Pain Questionnaire Data During Opioid Blockade with Naltrexone and Placebo During the Forearm Ischemia Task as well as the Statistical Signicance Level of the Drug Effects Variable Total pain rating index (045) Sensory pain rating index (033) Affective pain rating index (012) Overall Pain Rating (0100) Present Pain Intensity (05) Naltrexone 15.3 (9.9) 13.0 (7.6) 2.3 (3.2) 75 (20) 2.6 (1.0) Placebo 13.4 (9.8) 11.7 (8.3) 1.8 (2.5) 70 (19) 2.7 (1.1) Drug effect P .25 .39 .27 .45 .44

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signicant condition effect also emerged for heart rate, F(6, 11) = 12.83, p = .001, 2 = .875; heart rates were faster during the rst baseline than the second baseline and cold pressor tasks, which in turn, were faster than during the ischemic task and recovery. None of the drug or sex effects were signicant. DISCUSSION Although subgroup analyses provided limited evidence that ischemic pain was somewhat greater during naltrexone than placebo in men, overall the results of the current study suggest that the experience of both cold pain and ischemic pain was not augmented during pharmacological blockade of opioid receptors in patients with essential hypertension. These results broadly agree with the nding of a previous study showing that naloxone did not change mechanical pain in borderline hypertension (Schobel et al., 1998). However, the results of these two studies stand in distinct contrast to the existing evidence of reversal of hypertensive hypoalgesia through opiate blockade in laboratory animal studies (Maixner et al., 1982; Naranjo and Fuentes, 1985; Saavedra, 1981; Sitsen and de Jong, 1983, 1984; Zamir and Segal, 1979; Zamir, Simantov, and Segal, 1980). The current study also showed that blood pressure and heart rate, both at rest and in response to cold and ischemic challenge, were not affected by

naltrexone. These observations are compatible with previous studies reporting that opioid blockade moderates exercise-induced cardiovascular responses in normotensive but not hypertensive individuals (Hara and Floras, 1995) and that opioid blockade attenuates stress-induced pressor responses in individuals with low-normal resting blood pressure but not in those with high-normal pressure (McCubbin Sunwit, and William, 1988). Taken together, the results of the current and previous studies in humans are compatible with the hypothesis that hypertension in humans is characterised by insensitivity to centrally and/or peripherally acting opioids (France and Ditto, 1996; Feuerstein and Siren, 1987). The discrepancy in the effect of opioid blockade on pain in relation to blood pressure status in human and rodent studies may be attributable in part to the greater likelihood of opioid responsivity in animal studies. Whereas studies with laboratory animals provide consistent evidence for naloxone-reversed opiate activity, similar blockade paradigms have not yielded consistent ndings in humans. According to animal studies, uncontrollability may be a necessary factor in opioid activation, as shown in studies of learned helplessness and stress-induced analgesia (Maier, Sherman, Lewis, Terman, and Liebeskind, 1983; Maier, 1990). For instance, Maier and colleagues (1983) found that only conditions that allowed for learning-of-uncontrollability, such

Table IV. Mean (SD) Short-Form McGill Pain Questionnaire Data for Men and Women During Opioid Blockade with Naltrexone and Placebo During the Forearm Ischemia Task as well as the Statistical Signicance Level of the Drug by Sex Effects Men Variable Total pain rating index (045) Sensory pain rating index (033) Present pain intensity (05) Placebo 10.7 (9.0)a 9.2 (7.8) 2.0 (0.6)b Naltrexone 15.1 (9.6)a 12.8 (7.5) 2.4 (0.9) Women Placebo 16.9 (9.5) 14.7 (8.1) 3.6 (0.8)b Naltrexone 15.6 (10.1) 13.3 (7.8) 2.9 (0.8) Drug by sex effect p .05 .05 .02

Note. Means in the same row that share superscripts differ signicantly in the post-hoc comparison.

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Ring et al. increased controllability may limit the likelihood of producing signicant endogenous opiate mediated pain reduction in human studies. Previous research has demonstrated that experimental pain tasks, including cold pressor, are associated with opioid release in humans (e.g., Rosa et al., 1988). Although the current ndings that cold and ischemic pain were not different during placebo and naltrexone are compatible with opioid insensitivity in hypertension, as we did not measure circulating opioids to establish whether the tasks were sufciently provocative to trigger opioid release, the null ndings could also be explained by the absence of any opioidmediated analgesia. It should also be recognised that the number of participants tested was small and therefore sample size may have reduced the power to detect differences between opioid blockade and control. However, the effect sizes were small and post hoc power calculations indicated that we would have needed to test hundreds of participants to detect signicant effects of naltrexone versus placebo on pain. The null ndings are therefore most likely to be attributable to low effect sizes rather than small sample size. It has also been suggested that hypertensive hypoalgesia is mediated by opioid hyposensitivity. However, any interpretation of hyposensitivity must remain speculative without comparative data from a normotensive control group. With this in mind, it should be noted that other studies have failed to detect changes in mechanical and ischemic pain (Bruehl et al., 2002) as well as electrocutaneous pain (France et al., 2005) with opioid blockade in normotensive individuals which might, in the absence of corroborative blood data concerning plasma opioid concentrations, be interpreted as indicating opioid insensitivity in normotensive individuals. Accordingly, denitive conclusions about relative sensitivity to opioids as a function of blood pressure status cannot be drawn at this time. The attenuation in pain during the performance of the secondary task compared to rest is in accordance with a substantial body of evidence documenting that pain is reduced by distraction in healthy individuals (alAbsi and Rokke, 1991; Edwards et al., in press; Miron et al., 1989; Petrovic et al., 2000; Villemure and Bushnell, 2002). To our knowledge, the current study is the rst to demonstrate that cold pain was attenuated by distraction in patients with hypertension. The results showing that a distracting secondary task reduced pain ratings suggests supraspinal modulation of pain in hypertension.

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Fig. 3. Mean (SE) systolic blood pressure (A), diastolic blood pressure (B) and heart rate for naltrexone and placebo sessions during the 5-min rest periods at the start of the session (1st Baseline), one-hour after tablet ingestion (2nd Baseline), and at the end of the session (Recovery), during the 2-min cold pressor tasks when rst relaxing (Cold Rest), when performing the distracting secondary task (Cold Distract), and when relaxing for a second time (Cold Rest), and during the 5-min forearm ischemia task (Ischemia).

as 20 min of intermittent footshock or 6080 trials of tailshock, were able to induce opioid analgesia. Obviously, humans have more control in experimental pain studies as they are always informed that they can discontinue a painful procedure at any time. In addition to differential opportunities for control, it is also arguable that laboratory pain paradigms are often more aversive in animal versus human studies. In sum, the combination of reduced aversiveness and

Pain in Hypertension ACKNOWLEDGMENTS This study was supported by NIH grant R01 HL64794. L. E. is a British Heart Foundation Fellow (FS/03/128). REFERENCES
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