Pain and Pain Treatment in AIDS Patients: A Longitudinal Study

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1 Vol. 19 No. 5 May 2000 Journal of Pain and Symptom Management 339 Original Article Pain and Pain Treatment in AIDS Patients: A Longitudinal Study Liv Merete Frich, RN and Finn Molke Borgbjerg, MD Department of Infectious Diseases and H:S Multidisciplinary Pain Center (L.M.F.), National Hospital, Copenhagen, Denmark; and The Pain Clinic (F.M.B.), Department of Anesthesiology, Bispebjerg University Hospital, Copenhagen, Denmark Abstract To determine the prevalence, incidence, and characteristics of pain connected with AIDS, 95 AIDS patients were enrolled in a prospective longitudinal study and interviewed every six months during a 2-year period or until death. The overall incidence of pain was 88%, and 69% of the patients suffered from constant pain interfering with daily living to a degree described as moderate or severe. The most common pain localizations were: extremities (32%), head (24%), upper gastrointestinal tract (23%) and lower gastrointestinal tract (22%). Pain conditions were connected to various opportunistic infections, Kaposi s sarcoma, or lymphoma. Pain in the extremities was predominantly of neuropathic origin (21%). The number of pain localizations increased significantly as death approached ( vs , p 0.03). The survival rate for patients without pain at entry was significantly higher than the survival rate of patients in pain, probably related to differences in the duration of AIDS at the time of inclusion. Sustained-release morphine preparations were prescribed in 29% of the patients. Of 39 patients (41%) who died in the department, 7 patients were prescribed continuous intravenous morphine infusion for pain treatment in the terminal phase and 20 patients received short-acting opioids. According to the Pain Management Index (PMI), the patients were insufficiently treated at the beginning of the study. Although the PMI improved significantly during the observation period, the patients felt that pain was not taken seriously by the physicians. However, the patients were convinced that treatment was optimal and, therefore, only 9% of the patients were dissatisfied. Patients were reluctant to take analgesics, primarily because of fear of addiction. J Pain Symptom Manage 2000;19: U.S. Cancer Pain Relief Committe, Keywords Pain, AIDS, incidence, prevalence, pain treatment Introduction The prevalence of pain in patients suffering from acquired immune deficiency syndrome (AIDS) in different hospital settings or in a home care setting is reported to vary between Address reprint requests to: Liv Frich, RN, Vestre Paradisvej 70, 2840 Holte, Denmark. Accepted for publication: June 17, % to 80%. 1 7 No reports exist in the literature concerning the incidence of pain in AIDS patients, and despite the high prevalence of pain, the published literature is scarce. The literature describing pain management in AIDS patients is based on clinical experience and the use of the World Health Organization (WHO) analgesic ladder approach. 4,5,8,9 The WHO approach is based on the assumption of no difference between the care of patients with AIDS U.S. Cancer Pain Relief Committee, /00/$ see front matter Published by Elsevier, New York, New York PII S (00)

2 340 Frich and Borgbjerg Vol. 19 No. 5 May 2000 and the care of patients with advanced cancer. 10 Because of the similarity in the medical, social, emotional, psychological, and psychiatric aspects of the pain condition, the guidelines recommend similar treatment of pain in AIDS and cancer patients. Treatment of underlying infections in AIDS patients may result in more effective pain relief than general measures alone. 11 In addition, AIDS patients often suffer from neuropathic pain, 2,4 6,12 and guidelines for pain treatment of AIDS patients should also consider these pain conditions. 4 The purpose of the present study was to determine the prevalence and the incidence of pain in a group of AIDS patients and to characterize pain and pain treatment during an observation period of two years. Methods Subjects AIDS patients who were treated at the Department of Infectious Diseases, National Hospital, Copenhagen during the first 3 months of 1994 were included. All patients were older than 18 years and had AIDS based on clinical AIDS-defining events. 13 The study was approved by the Regional Ethics Committee of Copenhagen and prior to participation all subjects signed an informed consent. Study Method Demographic features, including age, gender, infection route, nationality, AIDS-defining events, steady medical treatment, cause of death, and treatment of pain during the last two weeks and 24 hours before death were obtained from the patients medical records. The patients were interviewed at the time of inclusion and after 6, 12, 18, and 24 months or until death occurred. The interviews were semistructured and contained questions concerning pain etiology, localization, duration, frequency, quality, and intensity. Pain was considered disturbing if described as constant (or occurring several times a day) and interfering with daily life to a degree described by the patients as moderate or severe. Pain in total included intermittent pain or pain not interfering with daily living. Patients receiving analgesics were asked about medications. The origin of pain was derived from the patient s statements, confirmed, when possible, by information obtained from the medical records. Patients in pain were asked to determine interference with daily life as none, some or severe. Pain reports were only obtained if the patients related the pain to AIDS. Patients were asked about treatments, traditional or alternative, efficacy of the treatments and the degree to which they were satisfied with the treatment. Reports from patients regarding use of analgesics were recorded. Tricyclic antidepressants (TCA) and anticonvulsants were only registered as analgesics if they were used to obtain pain relief. Pain intensity was scored using a Visual Analogue Scale (VAS). Average pain for the last two weeks, as well as pain intensity when worst and least, were registered. An open question concerning the opinions of the patients about the pain treatment was posed at the end of the interview. Interviews were conducted by the same nurse in the outpatient clinic. Occasionally the interviews were obtained during hospital admission or in the patient s home. Adequacy of Analgesic Treatment According to the WHO guidelines for the management of pain in cancer, 14 pain treatment is considered adequate if congruence exists between the patient s reported level of pain and the type of the prescribed analgesic drugs. The Pain Management Index (PMI) 15 compares the prescribed analgesics with the pain intensity reported by the patient. To construct the index, the patient s rating on the pain when worst item and the analgesics prescribed are both assigned scores. The scores assigned to pain are 0 for no pain, 1 for mild pain (VAS 40), 2 for moderate pain (VAS 40 80) and 3 for severe pain (VAS 80). Using a similar procedure, the analgesics are classified according to the WHO analgesic ladder: Patients receiving so-called strong opioids are assigned a score of 3, patients receiving so-called weak opioids are assigned a score of 2, patients receiving nonopioid analgesics are assigned a score of 1, and patients taking no analgesics are assigned a score of 0. The method does not include the use of adjuvant analgesics, but, as described by Breitbart et al., 5 these drugs may be counted as nonopioid drugs, with the score 1. The PMI is computed by subtracting the assigned pain intensity score from the assigned score for the prescribed analgesics. The index

3 Vol. 19 No. 5 May 2000 Pain and Pain Treatment in AIDS Patients 341 ranges from 3 (a patient with disturbing pain, who is prescribed no analgesic) to 3 (a patient who does not report pain and is prescribed a strong analgesic). According to the WHO guidelines, scores of zero and above indicate adequate analgesic therapy, whereas scores in the negative range indicate inadequate analgesic therapy. Statistical Analysis Unless stated otherwise, all data are expressed as either mean SD or in percentage of the total number of patients participating in each interview. Statistical calculations were performed using Fishers exact test for categorical data, and Wilcoxon or Mann-Whitney rank-sum tests for paired or unpaired comparisons of two groups, respectively. Survival data were analyzed by lifetable analysis (Statistica, Statsoft ). Differences in survival time between the groups were computed by using a two-way ANOVA. Patient survival was measured both from the day of the AIDS-defining event until death and from inclusion to death. For all analyses, the level of significance was chosen to be p Results Patient Characteristics One hundred ten patients were treated at the department at the time of inclusion. Five patients were excluded due to unstable contacts with the department, nine patients were dying, and one patient was excluded due to a pre-existing chronic pain condition. Ninetyfive patients were included, 83 male and 12 female, age 40 9 years. Sixty-seven patients were alive at the second interview, 38 at the third, 24 at the fourth and 20 at the fifth. Interviews were obtainable in 61, 33, 21 and 18 patients at time 6, 12, 18, and 24 months, respectively. Patients who for other reasons could not be interviewed (patients who were terminal, demented, confused, had missed appointments or moved away) were only included in the survival statistics. This was the case in 6, 5, 3, and 2 patients at 6, 12, 18 and 24 months, respectively. Duration of AIDS (defined as the time from diagnosis of AIDS to the first interview) was months for patients in pain and months for patients without pain (p 0.05). The majority of the patients had contracted the disease sexually (90%), mainly through homosexual contact (73%). Three percent had a known history of intravenous drug abuse and were on a methadone maintenance program. Blood or blood-products infected 5%, and in 3% infection route was unknown. Eighty-seven percent of the patients were Danish, 4% Scandinavian, 5% African, and 3% miscellaneous. The main events for the AIDS diagnosis were pneumocystis carinii pneumonia (PCP) (40%), Kaposi s sarcoma (KS) (16%) and esophageal candidiasis (14%). Other events were HIV-wasting and toxoplasmosis (5% each), mycobacteria avium infection (MAI) and lymphoma (3% each), cytomegalovirus (CMV) and cryptosporidiosis (2% each), and miscellaneous 10%. The causes of death were HIV-wasting (19%), MAI (13%), CMV (5%), and unknown (14%). Three percent died for reasons not directly connected with AIDS (cardiac failure, chronic obstructive lung disease, and suicide). Twenty-one percent were alive at the end of the study. Antiviral Treatment Forty-seven patients (50%) were receiving antiviral chemotherapy (incidence). At the first interview, 44% received therapy (31% Retroviro monotherapy). After 6, 12 and 18 months the percentages were 33% (25%), 27% (19%), and 49% (34%), respectively. At 24 months, 50% (10 patients) received antiviral chemotherapy; only one patient received Retrovir monotherapy. Antiviral Treatment and Pain No correlation between antiviral therapy and the occurrence of pain was observed. At first interview, 40% of patients in pain and 50% of the pain-free patients received antiviral treatment. The Prevalence and Incidence of Pain Prevalence of pain at entry was 74%. Incidence of pain during the observation period was 88% (Table 1). The prevalence and incidence of disturbing pain were 51% and 69%, respectively. The incidence of non-disturbing pain was 19%, and the incidence of no pain at all was 12%. Pain Localization The pain localizations are shown in Table 1. The incidence of disturbing pain in the gas-

4 342 Frich and Borgbjerg Vol. 19 No. 5 May 2000 trointestinal (GI) tract was 45% (patients experiencing disturbing pain in either the upper GI tract or the lower GI tract or both). The number of pain localizations in each individual varied from one to five. At entry, the 71 patients reporting pain experienced an average of pain localizations. The number of pain localizations in patients attending more than one interview was at the first interview and at last interview (P NS). However, a significant increase in disturbing pain localizations was observed between the last two interviews before death or closure of the study, versus (p 0.03, n 26). Survival Rate A significant difference was observed in the survival time between patients without pain, and patients experiencing pain at the time of inclusion (p 0.001) (Fig.1). For patients experiencing disturbing or non-disturbing pain, the mean time from inclusion to death or termination of the study was 265 and 291 days respectively, and for pain-free patients, it was 494 days. This difference between patients experiencing pain and pain-free patients was statistically significant (p 0.001). The mean times from the AIDS diagnosis until death or the end of the study were 846, 912 and 903 days for patients with disturbing pain, non-disturbing pain and no pain, respectively (p 0.05). Pain Qualities, Origin, Intensity and Duration Patients reported pain qualities and assumed origin of their pain. The majority of patients with disturbing pain in the extremities (23% of 32%) experienced pain qualities corresponding to neuropathic pain (tingling, stabbing, shooting, and burning), and stated neuropathy as origin for their pain. In the upper GI tract, infections were the main origin (fungal infections in 12% of 23%, other infections in 3% of 23%) causing burning and scorching pain. Headaches (24%) were pressing and throbbing, and had various origins (6% of 24% were unknown), and abdominal pain had various origins, mainly opportunistic infections (8% of 23%), and various pain characteristics. Average pain scores during the last two weeks for worst and least pain intensity are shown in Table 2. VAS scores for worst pain (disturbing and not disturbing) in patients participating in at least two interviews (n 61) did not change significantly. Due to elimination of the pain source, 15% of the patients experienced pain only for a limited period of time. Patients who were pain-free at entry had a statistically significant risk of experiencing pain during the observation period (p 0.004, n 29). At the first interview, 66% of the patients had experienced pain for more than 3 months prior to inclusion and 67% of these reported disturbing pain. The duration of the pain periods could be determined for 35 patients (37%). In 22 patients, pain lasted between 2 weeks and 9 months; six patients had disturbing pain for 6 18 months, three patients experienced disturbing pain for months, and four patients had pain that lasted for more Table 1 Pain Prevalence, Incidence, and Localizations Reported by AIDS Patients Prevalence of pain a and pain localizations (%) Incidence of pain and pain localizations (%) Prevalence of disturbing b pain and pain localizations (%) Incidence of disturbing pain and pain localizations (%) % of all patients Extremities Subgroup stating neuropathic pain c Lower GI tract Upper GI tract Head Muscles or joints a Pain defined as any pain connected to the disease b Disturbing pain defined as constant pain or pain several times every day interfering with daily life to a degree described by the patient as moderate or severe. c Subgroup of patients experiencing neuropathic pain defined by patients stating neuropathy as a reason for their pain or patients with characteristic neuropathic pain qualities (burning, tingling, stabbing, or shooting) (n 95) GI, gastrointestinal

5 Vol. 19 No. 5 May 2000 Pain and Pain Treatment in AIDS Patients 343 Fig. 1. Survival rates for the population divided into 3 groups: disturbing pain, non-disturbing pain (pain) and no pain at the time of inclusion. A comparison between pain-free patients and patients experiencing pain revealed a significant difference (p 0.001). than two years. Neuropathic pain was predominant in 5 of 7 patients with long-lasting pain (more than one year). In 32%, the duration of pain could not be determined, the pain debut was more than 3 months prior to the first interview, or the patients were alive and reported pain at the last interview. Treatment Table 3 describes the number of patients receiving analgesic treatment and the type of analgesics used. Two patients received sustainedrelease morphine (SRM) at inclusion. Sixteen percent (15 patients) received SRM for a period during which they were interviewed at least one time. Thirteen percent (12 patients) were prescribed SRM in the period between their last interview and death, resulting in incidence of SRM treatment of 29%. The average duration of treatment with SRM was 2.4 months (range 1 5 months), not including patients starting treatment between their last interview and death. For patients alive at the end of the study, the average length of SRM treatment was 5 months (range 1 18 months). One of these patients stopped treatment, as the cause of pain was otherwise successfully treated. The pain treatment changed during the study period from mild analgesics used as needed to fixed scheduled treatment with sustained-released opioids. Pain Treatment During the Last 24 Hours Thirty-nine patients (41%) died during a hospital admission. Twenty patients received shortacting opioids during the last 24 hours. The drugs were primarily administered orally or intravenously, and in a few cases subcutaneously, intramuscularly or rectally. Non-opioid analgesic drugs were not used. Seven patients were prescribed continuous intravenous morphine infusions for terminal pain treatment. The intravenous morphine infusion was started hours before death (range hours). Pain treatment in these seven patients two weeks before death varied from SRM to no analgesics. Adequacy of Analgesic Treatment The average PMI scores in patients who attended at least two interviews and who had pain at entry were at the first interview and at the last interview, in the same patients. This increase in PMI scores is statistically significant (p 0.05, n 31). Adequate analgesic treatment according to the WHO guidelines increased from 23% to 64% (Table 4).

6 344 Frich and Borgbjerg Vol. 19 No. 5 May 2000 Table 2 VAS Scores for Average, Worst and Least Pain 1st Interview (N 95) 2nd Interview (N 64) 3rd Interview (N 37) 4th Interview (N 24) 5th Interview (N 20) Number of patients reporting disturbing a pain Patients reporting disturbing pain; VAS mean, during last 2 weeks Patients reporting disturbing pain; VAS mean, worst pain Patients reporting disturbing pain; Mean value of VAS scores of least pain Number of patients reporting not disturbing c pain Patients reporting not disturbing pain; VAS scores of worst pain (excluding 2) b (excluding 3) (excluding 1) (excluding 2) 53 mm mm mm mm 2 48 mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm 30 a Disturbing pain defined as constant pain or pain every day interfering with daily living to a degree described by the patient as moderate to severe. b Senile, terminal or missed patients are patients who according to the medical records were in stable analgesic therapy but unable to attend the interview. c Not disturbing pain defined as pain not existing every day or interfering with daily living. VAS, visual analogue scale. Patient Satisfaction Patients were asked to evaluate the pain treatment. At the first interview, 40% answered the question although only 11% received stable analgesic treatment. Twenty-four percent were satisfied, 13% found the treatment acceptable, and 3% were not satisfied. Throughout the observation period, 9% of the patients stated not satisfied. No patients stated not satisfied for more than one interview. Of the patients who were satisfied, 79% had constant pain, 57% had had pain for more than three months, and 39% received fixed scheduled analgesic treatment. The percentages were nearly the same in the group that described the therapies acceptable. In the not satisfied group, 88% had constant pain, 60% had pain for more than 3 months, and 80% received fixed scheduled analgesic treatment. At the end of each interview, the patients were asked for comments regarding the pain treatment. Ninety-one statements were obtained during the entire observation period. The following comments were frequently stated: the physician was regarded as an authority and was responsible for the treatment; pain was not taken seriously by the physicians; contact with the same physician or nurse was preferred; patients believed that they received optimal treatment therefore accepted living with pain. Patients were reluctant to take analgesics ( Taught not to take it, want to save it for later, afraid of having used up the possibility if pain gets unbearable, afraid of addiction ), and they were afraid of side effects (sedation, dizziness, constipation, nausea) if dosages needed to be increased. Not enough analgesics prescribed was stated by patients stating unsatisfied. Alternative Treatment At the first interview, 8% had tried alternative treatments (acupuncture, healing, visualization, massage) for AIDS-related symptoms. The use of alternative treatment was sparse at the following interviews. Some of the patients reported increased well-being as a result of alternative treatment and in one patient, pain relief was obtained by healing. Discussion This longitudinal study is to our knowledge the first report describing the incidence of pain in a non-selected group of AIDS patients. Comparisons between different studies in literature are difficult for several reasons: differences in description of pain localizations, differences in pain definitions, different selection of samples, and varied demographic differences across groups. Although these differences influence results, the overall prevalence of pain and the main localization in the present study are comparable to the published literature. 1,3,5,7,8,12,15 The similar findings despite the different methods of assessment are not surprising; as defined by WHO, pain is a subjective sensation and experience.

7 Vol. 19 No. 5 May 2000 Pain and Pain Treatment in AIDS Patients 345 Table 3 Analgesic Treatment: Prevalence and Incidence a Visit, month Incidence Number of patients % (number of patients) Steady pain treatment as needed b 11 (10) 25 (16) 22 (8) 21 (5) 45 (9) 30 (29) Strong opioids Sustained-Release morphine 2 (2) 8 (5) 10 (4) 8 (2) 30 (6) 29 (27) Steady treatment with short-acting strong opioids 3 (3) 8 (5) 5 (2) 4 (1) 5 (1) 4 (4) Administered as needed steady treatment 2 (2) 8 (5) 5 (2) 8 (2) 20 (4) 6 (6) Weak opioids Codeine, dextropropoxyphen, tramadol 2 (2) 4 (2) 5 (2) 4 (1) 5 (1) 6 (6) Administered as needed 1 (1) 2 (1) 5 (2) 4 (1) 5 (1) Mild analgesics Long-acting ACM, NSAID 0 4 (2) (1) ACM, ASA. (Steady treatment round the clock ) 2 (2) 2 (1) NSAID or ACM as needed 32 (30) 19 (12) 11 (4) 8 (2) 15 (3) 27 (26) Antidepressants as analgesics Monotherapy 1 (1) 2 (1) 0 4 (1) 5 (1) 3 (3) In combination with analgesics 2 (2) 4 (2) 5 (2) 4 (1) 10 (2) 4 (4) a For both prevalence and incidence, only the most potent analgesic is included. b As needed treatment or treatment with milder analgesics in one interview changed to steady or more potent analgesic in a later interview are included as the most potent/steady treatment. ACM, acetaminophen; ASA, acetylsalicylic acid; NSAID, nonsteroidal anti-inflammatory drugs. Our population is atypical regarding the infection route, with only 3% being infected by intravenous drug administration. This percentage is low compared with the literature, in which 50% of the patients were infected by the intravenous route. This could be due to a general low percentage of intravenously infected patients in Denmark (during the last 3 years only 10% of the newly infected persons were infected by the IV route 16 ) or due to the low percentage of intravenous drug users in the admission area of the hospital. Needles and syringes have been provided for free at every pharmacy for the last 12 years, which could be part of the reason for the low percentage of HIV-infected drug users. Intravenous drug abuse has been described as a predictive factor for undertreatment of pain, 5 but previous results 7 and the present investigation confirm that undertreatment is a common feature in all AIDS patients. There is a significant risk of developing pain in patients with no pain at entry and a significant increase of disturbing pain localizations during the last year of the patient s life. The occurrence of pain associated with disease progression has been described, 2 and new pain conditions were shown to be more frequent in progressed HIV or AIDS. Although these results were observed in a population of HIV-infected men, they correlate well with the results of the present study. The survival rate for patients without pain at entry is significantly higher compared with the survival rate of patients with pain (p 0.001). This difference is probably caused by a difference in the duration of AIDS at the time of in- Table 4 Adequacy of Pain Therapy Calculated in Patients with Disturbing Pain 0 n 48 6 Months n Months n months n 9 24 months n 11 Patients stating disturbing pain receiving adequate treatment 23% 31% 36% 33% 64% Patients stating disturbing pain receiving inadequate treatment 77% 69% 64% 67% 36%

8 346 Frich and Borgbjerg Vol. 19 No. 5 May 2000 clusion, i.e. patients without pain have had AIDS for a shorter period than patients with pain, although the difference is non-significant. Pain duration varies. The predominant location and quality in patients with long-lasting pain indicates the importance of neuropathy in the extremities. Further stratification of the sample would not be statistically correct, i.e. the number of patients in each sample would be too small. The percentages of opioid-treated patients is a snapshot of the local prescribing procedures, but the percentages in this study are very similar to the percentages in other studies. 5 7 The use of adjuvant analgesics (antidepressants and anticonvulsants) is sparse, as previously has been reported in AIDS patients. 3,5 It has been pointed out that the role of these drugs is especially important because of the neuropathic features in AIDS-associated pain conditions. 5 The specific importance of adjuvant analgesics in AIDS-associated pain conditions remains to be established. Seventy-seven percent of the patients had negative PMI scores at the first interview, indicating inadequate analgesic treatment. PMI scores similar to this (85%) have previously been reported. 5,7 The limitations of the PMI as an index of analgesic adequacy must be acknowledged. 5 The PMI reflects a relatively simple approach to assessing adequacy of analgesic therapy, but it does not incorporate dosage, the use of adjuvant analgesics, or non-pharmacological analgesic interventions. However, as no better method is available, the PMI score represents a practical instrument. One reason for the remarkable increase of the PMI during the study period could be that patients in pain received more adequate treatment, or it might reflect that the need for, thus treatment with, analgesics increase with time. These figures are not representative, as they reflect the practice at one specific hospital at a specific time. The patient comments reveal a reluctance against proceeding to steady treatment with strong opioids and confirms the observation that physicians are conservative regarding analgesic treatment in AIDS patients, despite previous published recommendations. 4 7,10,17 Lack of knowledge may also be an important factor. The comments also show that the patients are reluctant to receive analgesics. The reasons are attitudes against pharmacological treatment, lack of knowledge about existing possibilities, fear of addiction, and fear of having exhausted the possibility to be provided adequate pain treatment when pain increases or during the terminal phase. Lebovits et al. 3 showed that AIDS patients in pain are hospitalized for significantly longer periods than those without pain. This is not unique for patients with AIDS. 18 The life span of HIV-infected patients can now be prolonged by antiviral therapy and prophylactic therapy for opportunistic infections, 19 and this makes quality of life an increasingly important issue. Significant relationships between pain, psychological well-being and quality of life have been described. 20 All these observations confirm the need of providing adequate treatment of pain to patients with AIDS. More focus should be placed on symptom relief along with active treatment of underlying infections. The influence of new antiviral therapies on painful conditions is yet to be determined and specific effective pain treatments for persisting pain are yet to be described. In conclusion, the incidence of disturbing pain in AIDS patients is high. The most common pain localizations are the extremities, the GI tract, and the head. Often pain is present for less than a year, but when prolonged, neuropathic pain is usually predominant. There is a significant risk for patients without pain of later experiencing periods of disturbing pain, and there is a statistically significant increase in the number of disturbing pain localizations during the last six months before death. PMI scores reveal a high level of inadequate analgesic treatment, but for this group of patients treatment improved remarkably during the observation period. Improvement of analgesic therapy will require education both among medical staff and patients, because the patients are reluctant to accept analgesics. Acknowledgments This research was financially supported by the Lundbeck foundation via The Centre for Nursing Research of the University Hospitals of Copenhagen., The Department of Infectious Diseases (Rigshospitalet), The Danish AIDS Foundation and Pharmacia Upjohn A/S Denmark.

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