ASSESSMENT OF ANALGESIC EFFECTS OF DIFFERENT INITIAL DOSES
OF TRANSDERMAL BUPRENORPHINE IN THE TREATMENT OF CHRONIC
PAIN IN THE ELDERLY DIAGNOSED WITH OSTEOARTHRITIS

Pain in the elderly is a frequent symptom reducing mobility and negatively affecting patients’ quality of life (1). Chronic pain occurs in 25 – 70% of the general population of people over 65 years old and in 71 – 83% of elderly patients staying in long-term care (2). In this group of patients, pain is frequently induced by changes in joints and skeletal system and reported in many parts of the body (3, 4). Pathophysiology of chronic pain is complex including changes in the functioning of the peripheral and central nervous system with significant role of microglia, astrocytes, and oligodendrocytes (5). Pain considerably impairs mobility, increases the risk of falls and development of depressive and anxiety disorders, causes sleep disturbances and limits social interaction (6, 7). Management of chronic pain in the elderly is hindered by physiological changes influencing metabolism and a greater risk of potential adverse effects of analgesics and other drugs, polypharmacy, as well as common concurrent diseases, including cognitive dysfunction (8), which limits the effectiveness of pharmacotherapy in this population (9). In treatment of chronic pain of severe intensity: 6 – 10 in NRS (Numerical Rating Scale), the use of third step opioid of the World Health Organization (WHO) analgesic ladder is recommended, including buprenorphine (10). However, due to the concerns of patients, caregivers and doctors (opioidophobia) associated mainly with adverse effects and addiction, the use of opioids in elderly patients is still limited (11). In this group of patients, non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used despite a greater risk of adverse effects and numerous contraindications (12). The aim of the study was to evaluate analgesia and the quality of life during treatment of chronic pain of severe intensity (NRS > 5) with different initial doses of transdermal buprenorphine in elderly patients diagnosed with degenerative joint disease.

PATIENTS AND METHODS

The study was conducted among patients hospitalized in the Department of Geriatrics (over 64 years old) diagnosed with chronic pain of severe intensity (NRS > 5) induced by degenerative joint disease. The duration of the study was 10 days. Every day for 10 days the Brief Pain Inventory - Short Form (13) was used to evaluate pain intensity and the impact of pain on patients’ everyday activities. The DN4 (Douleur Neuropathique en 4 Questionnaire) was used on the first day of the study in order to identify the components of neuropathic pain (14) and MMSE (the Mini-Mental State Examination) was used to evaluate cognitive function (15).

Brief Pain Inventory - Short Form (BPI-SF) is a 9 item self-administered questionnaire used to evaluate the severity of a patient’s pain and the impact of this pain on the patient’s daily functioning. The patient is asked to rate their worst, least, average, and current pain intensity, list current treatments and their perceived effectiveness, and rate the degree that pain interferes with general activity, mood, walking ability, normal work, relations with other persons, sleep, and enjoyment of life on a 10 point scale (13).

Mini-Mental State Exam (MMSE) is a widely used test of cognitive function among the elderly. It includes tests of orientation, attention, memory, language and visual-spatial skills. Any result below 24 points (out of 30) indicates the possibility of cognitive impairment of dementia (15).

The DN4 consisting of 10 items, was used to estimate the presence of the neuropathic component of chronic pain. The first 7 items of the scale concern the presence of the symptoms of pain which are characterized by: burning, painful cold, electric shock, tingling, pins and needles, numbness and itching. The next 3 items of the scale are associated with physical examination and include hypoesthesia to touch, hypoesthesia to pinprick, pain caused or increased by brushing. If the score in the questionnaire supported by yes answers was greater than or equal to 4, the patient is qualified for the diagnosis of neuropathic pain (14, 16).

Sixty patients were enrolled, and randomly assigned to one of the three groups of 20 (block randomization) (Fig. 1). In group 1, a starting dose for the treatment with transdermal buprenorphine was 8.75 µg/h, in group 2 – 17.5 µg/h, and in group 3 – 35 µg/h. According to the Summary of Product Characteristics (SmPC) transdermal buprenorphine patches used in this study should be changed at the latest every 72 h and a first evaluation of analgesic effect of a given patch strength can be done after 24 h. Transdermal buprenorphine was used every 72 h with the possibility of increasing the dose every 48 h, every 60 h or every 72 h. Patients in the study did not know the dose of transdermal buprenorphine used (single blinding). Doses of buprenorphine were increased until achieving satisfactory analgesia (NRS ≤ 4) with acceptable adverse effects according to the scheme:

Group 1: 8.75 → 17.5 → 35 → 52.5 → 70 µg/h

Group 2: 17.5 → 35 → 52.5 → 70 µg/h

Group 3: 35 → 52.5 → 70 µg/h

Fig. 1. Flowchart of the study.

In order to obtain starting doses of 17.5 µg/h and 8.75 µg/h, a patch of 35 µg/h was divided into 2 and 4 equal parts, respectively (this was off-label procedure). In cases where satisfactory pain relief was not achieved (NRS > 4) and/or severe adverse effects occurred, and/or patients resigned, the study was discontinued. In the treatment of breakthrough pain buprenorphine sublingual tablets were used as a single dose of 0.2 mg in all 3 patient groups. Patients were allowed to continue previously recommended adjuvants analgesics, and drugs and doses used were not changed during the whole study period. All patients were administered lactulose at the dose of 20 g per day for the prevention of constipation. In case of lactulose intolerance, macrogol at the dose of 10 g per day was administered. If constipation occurred despite preventive treatment implemented, glycerin suppository (on day 2 in the absence of stool) and an enema (on day 3 in the absence of stool) were additionally used. Antiemetics were not used as prophylaxis. In cases of nausea and vomiting, metoclopramide was administered parenterally.

Patients excluded from the study were: those over 65 years old, patients without pain or with pain ≤ 5 in the NRS, patients with cognitive dysfunction and dementia (MMSE < 24 points), patients with at least double elevated normal levels of aminotransferase and bilirubin, cancer patients, those previously treated with buprenorphine and/or other opioid from the third step of the WHO analgesic ladder, patients who could not be administered drugs transdermally and/or sublingually. Patients excluded from the study were also: patients with hypersensitivity to buprenorphine and/or any other excipient, patients with current history and/or a past history of opioid dependence and withdrawal syndrome, patients with present or potential respiratory failure, patients treated with MAO inhibitors within the last 14 days, and patients diagnosed with myasthenia gravis.

The study protocol was approved by the Bioethics Committee of the Regional Medical Council of the Great Poland Chamber of Physicians and Dentists in Poznan (consent number 14/2016).

Statistical analysis

Data were analyzed statistically with the data analysis software system Statistics, version 13, StatSoft Inc., Tulsa, USA. A statistical description of quantitative variables was created with the use of measures of central tendency - the arithmetical mean, and dispersion with the use of a standard deviation. Qualitative variables were expressed with numbers and percentages. Statistical inference was conducted with the use of parametric tests after prior checking of data distribution. The data was expressed on the interval scale (the results of the questionnaires) and obtained with the use of standard research tools and the data distribution did not deviate far from normal distribution (the analysis of variance ANOVA was used). Repeated measures analysis of variance was used to examine the dynamics of variables. The significance level was set at 0.05 to establish criteria for the rejection of the null hypothesis in all verifications of hypotheses.

RESULTS

The mean age of patients was 81.6 years (range 67 – 95) years. Thirteen men (21.67%) and 47 (78.33%) women were enrolled, 17 (28.33%) living in villages and 43 (71.67%) in cities. The main reason for admission to the hospital was severe chronic pain. A total of 5.7 concurrent diseases per patient were diagnosed, most frequent being cardiovascular diseases in 52 (86.6%) patients), type 2 diabetes in 22 (36.6%) patients and chronic kidney disease in 21 (35%) patients (Table 1).

Table 1. Characteristics of patients enrolled in the study.

Group 1 - starting dose of transdermal buprenorphine 8.75 µg/h; group 2 - starting dose of transdermal buprenorphine 17.5 µg/h; group 3 - starting dose of transdermal buprenorphine 35 µg/h.

Before the study, NSAIDs 46 (76.6%) patients, paracetamol 35 (58.3%) patients, tramadol 27 (45%) patients and metamizole 8 (13.3%) patients were most frequently used. Four (6.6%) patients did not use pain medications. The range of daily doses used before the study for paracetamol was 650 – 3000 mg, for tramadol 75 – 400 mg, for metamizole 500 – 1500 mg. The range of daily doses of the most commonly used NSAIDs were 50 – 100 mg for diclofenac, 100 – 300 mg for ketoprofen, 25 – 100 mg for dexketoprofen, 500 – 1500 mg for naproxen. Among those treated with NSAIDs, 19 (31.6%) patients took 2 or more NSAIDs, and 36 (78.3%) had concurrent diseases which contraindicated the use of NSAIDs according to the SmPC (Table 2).

Table 2. Analgesics used before the study.

Group 1 - starting dose of transdermal buprenorphine 8.75 µg/h; group 2 - starting dose of transdermal buprenorphine 17.5 µg/h; group 3 - starting dose of transdermal buprenorphine 35 µg/h.

Pain was usually located in several joints (an average of 4.3 joints per patient) and most frequently located in the spine 51 (85%) patients, knee joints 39 (65%) and hip joints 36 (60%) patients.

An average final dose of transdermal buprenorphine in all the patients was 28.6 µg/h. A mean dose of sublingual buprenorphine per patient was 0.48 mg during the whole study period (Table 3).

Table 3. Doses of transdermal and sublingual buprenorphine used in the study in individual groups.

Group 1 - starting dose of transdermal buprenorphine 8.75 µg/h; group 2 - starting dose of transdermal buprenorphine 17.5 µg/h; group 3 - starting dose of transdermal buprenorphine 35 µg/h.

Out of sixty patients 52 (86.6%) completed the study. A total 8 patients discontinued the study due to adverse effects (Table 4). The most common cause of discontinuation of the study was confusion observed in 7 patients. No skin toxicities have been observed.

Table 4. Initial and final doses of buprenorphine used in patients who discontinued the study and causes of discontinuation.

The DN4 was used to estimate the presence of neuropathic component of chronic pain. Twenty-seven (45%) patients obtained a positive score (³ 4). Most patients obtained a limit value of 4 – 17 (28.3%) patients. Most common „yes” answers in the DN4 test were: electric shocks - 24 (40%) patients, pins and needles - 30 (50%) patients, numbness - 25 (41.6%) patients, and pain caused by brushing - 27 (45%) patients. One patient (1.66%) took venlafaxine previously to treat depression. No differences regarding DN4 scores were find between patient groups.

A change of a buprenorphine patch initial dose was required because of pain in 6 (35%) patients in group 1, in 5 (25%) patients in group 2, and in 4 (20%) patients in group 3. In the evaluation of pain according to the BPI-SF, a decrease in pain intensity was observed in each patient group during the whole study period with no differences between patient groups (Table 5).

Table 5. Mean values of pain categories of the BPI-SF at baseline (day 1) and at the study completion (day 10) in all patients and in individual patient groups.

Pain relief: 0 - no pain relief; 100 - a complete pain relief; higher scores denote more intense pain.
Group 1 - starting dose of transdermal buprenorphine 8.75 µg/h; group 2 - starting dose of transdermal buprenorphine 17.5 µg/h; group 3 - starting dose of transdermal buprenorphine 35 µg/h.

Pain intensity decreased in all categories, i.e. pain at its worst (Fig. 2), pain at its least, pain on the average (Fig. 3), pain right now, and pain relief improved during the treatment used (Table 6).

Fig. 2.Pain at its worst (NRS in the BPI-SF) considering patient groups. Effect of time p < 0.0001; interaction of treatment and time p = 0.685. Vertical bars denote 0.95 confidence intervals. Group 1 - starting dose of transdermal buprenorphine 8.75 µg/h; group 2 - starting dose of transdermal buprenorphine 17.5 µg/h; group 3 - starting dose of transdermal buprenorphine 35 µg/h.

Fig. 3. Pain on the average (NRS of the BPI - SF) considering patient groups. Effect of time p < 0.0001; interaction of interaction of treatment and time p = 0.072. Vertical bars denote 0.95 confidence intervals. Group 1 - starting dose of transdermal buprenorphine 8.75 µg/h. Group 2 - starting dose of transdermal buprenorphine 17.5 µg/h; group 3 - starting dose of transdermal buprenorphine 35 µg/h.

Table 6. The impact of buprenorphine treatment on pain categories of the BPI-SF at baseline (day 1) and at the study completion (day 10), considering statistical significance.

NRS, Numerical Rating Scale. Pain relief: 0 - no pain relief, 100 - a complete pain relief. Higher scores denote more intense pain.

Regarding pain relief time effect and interaction of treatment and time were considered significant (Fig. 4).

Fig. 4.Pain relief (%) considering patient group. Effect of time p < 0.0001; interaction of interaction of treatment and time p = 0.003. Vertical bars denote 0.95 confidence intervals. Group 1 - starting dose of transdermal buprenorphine 8.75 µg/h; group 2 - starting dose of transdermal buprenorphine 17.5 µg/h; group 3 - starting dose of transdermal buprenorphine 35 µg/h.

The impact of buprenorphine treatment on categories other than pain according to the BPI-SF: general activity (Fig. 5), mood (Fig. 6), walking ability, relations with other people, sleep, and enjoyment of life, indicated a reduction of pain interference (according to NRS: 0 - no interference; 10 - pain completely interferes) with no differences between patient groups (Table 7). In each category, a significant improvement was observed during the study period (Table 8).

Fig. 5.Pain interference with general activity according to NRS of BPI-SF (0 - no pain interference; 10 - complete pain interference) considering patient groups. Effect of time p < 0.0001; interaction of treatment and time p = 0.595. Vertical bars denote 0.95 confidence intervals. Group 1 - starting dose of transdermal buprenorphine 8.75 µg/h; group 2 - starting dose of transdermal buprenorphine 17.5 µg/h; group 3 - starting dose of transdermal buprenorphine 35 µg/h.

Fig. 6.Pain interference with mood according to the NRS of BPI-SF (0 - no pain interference; 10 - complete pain interference) considering patient groups. Time effect p < 0.0001; interaction of treatment and time p = 0.863. Vertical bars denote 0.95 confidence intervals. Group 1 - starting dose of transdermal buprenorphine 8.75 µg/h; group 2 - starting dose of transdermal buprenorphine 17.5 µg/h; group 3 - starting dose of transdermal buprenorphine 35 µg/h.

Table 7. The evaluation of buprenorphine treatment on categories other than pain in the BPI-F (mean values) at baseline (day 1) and treatment completion (day 10) considering patient groups.

Higher scores denote more intense pain interference.

Table 8. The evaluation of buprenorphine treatment on categories other than pain in the BPI-SF (mean values and standard deviation) at baseline (day 1) and treatment completion (day 10) considering statistical significance.

Higher scores denote more intense pain interference. NRS, Numerical Rating Scale.

In pain interference item with sleep, an interaction of treatment and time was significant (Fig. 7).

Fig. 7. Pain interference with sleep according to NRS of BPI-SF (0 - no pain interference; 10 - complete pain interference) considering patient groups.- Effect of time p < 0.0001; interaction of treatment and time p = 0.009. Vertical bars denote 0.95 confidence intervals. Group 1 - starting dose of transdermal buprenorphine 8.75 µg/h; group 2 - starting dose of transdermal buprenorphine 17.5 µg/h; group 3 - starting dose of transdermal buprenorphine 35 µg/h.

DISCUSSION

The use of transdermal buprenorphine in this study provided a significant reduction of pain intensity in each group of patients in all the categories evaluated: pain at its worst, pain at its least, pain on the average, pain right now as well as an increase in a percentage relief of pain regardless of an initial dose of transdermal buprenorphine. A change of a buprenorphine patch strength was required because of pain in 6 patients in group 1 treated with a starting dose of 8.75 µg/h, in 5 patients in group 2 treated with an initial dose of 17.5 µg/h, and in 4 patients in group 3 treated with a starting dose of 35 µg/h. The mean value of pain intensity at baseline was 8.45 and 5.9 (both in the NRS) for pain at its worst and pain on the average, respectively, which indicates that the pain was of severe intensity. Pain was located most frequently in the spine, knee joints, and hip joints.

Furthermore, a reduction of baseline pain interference with general activity, mood, walking ability, relations with other people, sleep and enjoyment of life in each group of patients regardless of an initial dose of transdermal buprenorphine was observed. The mean age of all patients equalled 81.6 years with a total of 5.7 concurrent diseases per one patient diagnosed. Patients qualified for the study and randomized for individual groups did not differ significantly with respect to age, gender, place of residence, education and the number and type of concurrent diseases. Therefore, transdermal buprenorphine seems to be an effective opioid analgesic in this older patient cohort.

An average final dose of transdermal buprenorphine in all patients was 28.6 µg/h. However, an average final dose of transdermal buprenorphine was quite different depending on the initial dose of transdermal buprenorphine. In group 1, which started with a dose of 8.75 µg/h it equalled 20.26 µg/h, in group 2, which started with a dose of 17.5 µg/h it was 27.12 µg/h, and in group 3, which started at a dose of 35 µg/h it equalled 43.08 µg/h. It is difficult to interpret these differences as at baseline and during the treatment these patient groups did not differ regarding pain intensity and neuropathic pain component assessed by DN4. However, a possible explanation might be the fact that only few patients from all groups required increments of initial doses of buprenorphine patches because of pain: 6 patients in group 1, 5 patients in group 2, and 4 patients in group 3. The use of sublingual buprenorphine in the treatment of breakthrough pain per one patient was low during the whole study period in all patient groups (0.48 mg) as an indirect indicator of effective analgesia; it was very similar in group 1 and 3 (0.43 mg and 0.42 mg, respectively, which equals approximately 2 tablets 0.2 mg) and larger in group 2 (0.62 mg, which equals approximately 3 tablets 0.2 mg). This suggests that regular dosing of transdermal buprenorphine played a major role in achieving effective analgesia, whereas rescue buprenorphine sublingual tablets played a minor role.

Among 8 patients who discontinued the treatment with transdermal buprenorphine due to adverse effects, confusion, drowsiness and vomiting were observed in 7 patients who started at a dose of 35 µg/h. Confusion (probably as a result of increased drug absorption due to fever) was observed in one patient who started treatment at a dose of 8.75 µg/h. Due to the fact that analgesia was similar in all groups of patients, and the severity of adverse effects, forcing the treatment to be discontinued, was particularly visible in the groups of patients starting treatment at 35 µg/h, it seems that a lower initial doses (17.5 µg/h or 8.75 µg/h) are probably safer in the elderly (17).

In Poland, the smallest dose of transdermal buprenorphine patch is 35 µg/h (21). However, a patch of 35 µg/h is frequently cut to a half (17.5 µg/h) and sometimes to 1/4 (8.75 µg/h) (these are off-label procedures), because of the lack of lower doses available in other European countries and in the USA (5 µg/h, 10 µg/h, 20 µg/h), which are associated with a lower risk of adverse effects (18-20). Transdermal buprenorphine patches available in Poland are of a matrix structure, which, in contrast to reservoir system patches, do not influence drug release in the case of cutting.

Chronic pain in the elderly is most frequently located in the spine area in a higher percentage of females and in those less educated (22, 23). Negative consequences of long-term chronic severe pain correlate directly with low self-esteem related to health and quality of life, disability, tendency to falls, depression, sleep disorders and limited social interaction (6, 7, 10). Effective treatment of pain results in a significant improvement of the above mentioned general parameters associated with pain (24). Additionally, a reduction of pain intensity also enables physiotherapeutic activities, and, in consequence, an improvement of psychomotor performance and a return to family and social life (25). Increased patients’ activity and exercise may provide additional analgesic effects through activation of different endogenous systems, which release opioids, nitric oxide, serotonin, catecholamines, endocannabinoids, and anti-inflammatory cytokines (26). In this regard, the resistance against the use of opioids to treat non-cancer pain in the elderly can be challenged. Reports on adverse effects associated with the use of opioids in the treatment of pain in elderly patients are inconclusive (27). It has been stressed, however, that in patients suffering from severe pain, potentially harmful effects of opioids, particularly with respect to cognitive function, are compensated by an improvement of general activity associated with effective pain treatment (28).

The efficacy of transdermal buprenorphine in the treatment of chronic pain is well documented, also in patients with a neuropathic component of pain, nevertheless most randomized studies are limited to patients with an average age of 60 years (29-31). In comparison to other opioids, buprenorphine is characterized by a smaller risk of adverse effects such as cognitive impairment and gastrointestinal symptoms, in particular constipation; immunosuppression and endocrinopathy as well as respiratory depression (32). Buprenorphine is an effective and safe opioid analgesic in elderly patients regarding changes in metabolism and renal function (21). A low risk of drug interaction and addiction also support buprenorphine use in this group of patients (29). Transdermal route has many benefits: ease of administration by both patients and caregivers, greater patient compliance, a smaller risk of toxicity and accidental omission or double dosing, which are essential in patients with cognitive impairment, and preferred route of administration in elderly patients (30). Additionally, transdermal administration is also appropriate in patients who do not tolerate a large number of drugs administered orally or cannot receive drugs via this route for various reasons (31). Transdermal administration is more comfortable for patients and requires little staff and family involvement. The benefit of transdermal administration, particularly for elderly patients, is a slow increase of plasma concentration without a sudden peak, which results in a smaller number of adverse effects (27). However, transdermal system is not recommended in patients with fever, which increases the permeability of the skin and promotes the absorption of the drug and in consequence may lead to symptoms of overdose (32). Furthermore, transdermal formulation may induce local skin symptoms, which were not observed in our study (33).

Concurrent cardiovascular diseases were present in 52 (86.6%) patients. A possible correlation between the presence of chronic pain and an increased prevalence of cardiovascular diseases in the elderly was described (34-36). A number of areas of pain may be essential for the degree of cardiovascular morbidity, comparing the results obtained in groups of patients who reported chronic pain in more than four areas of the body with the results of patients who reported chronic pain in one location (37, 38). Establishing a casual link is difficult due to a percentage of patients with cardiovascular diseases and chronic pain increasing with age.

A general tendency to overuse and misuse NSAIDs should not be overlooked, as these are drugs with a documented negative impact on the cardiovascular system (39). NSAIDs were most frequently used in the treatment of chronic pain before the study - 46 patients (76.6%) of whom 19 (31.6%) took 2 or more NSAIDs (either OTC or prescribed) simultaneously, which is considered inadvisable. Furthermore, NSAIDs were contraindicated in 36 (78.3%) patients who used them, in line with the SmPC. A high percentage of elderly patients who use NSAIDs in the treatment of chronic pain connected with osteoarthritis was described (40). Although NSAIDs can be an effective way of treating pain and coexisting inflammation, the elderly are at an increased risk of adverse effects because of a loss of physiological organ reserves, concurrent diseases, common use of multiple drugs, polypharmacy, and changes in pharmacokinetics (12, 42).

Limitations of the study include a modest patients sample, a short period of the study, recruiting patients from one department, and a lack of blinding physicians regarding initial doses of transdermal buprenorphine.

Summarizing: the use of transdermal buprenorphine in the treatment of chronic pain of severe intensity in elderly patients diagnosed with degenerative joint disease provided effective analgesia regardless of an initial dose and coexisting component of neuropathic pain. Buprenorphine treatment reduced pain interference with general activity, mood, walking ability, relations with other people, sleep, and enjoyment of life. Treatment tolerance seems to be better with lower initial doses of transdermal buprenorphine: 8.75 µg/h and 17.5 µg/h in comparison with the dose of 35 µg/h.

Source of funding: The study has no funding.

Conflict of interests: None declared.

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