The effect of transdermal fentanyl treatment on serum cortisol concentrations in patients with non-cancer pain

The effect of transdermal fentanyl treatment on serum cortisol concentrations in patients with non-cancer pain

Vol. 28 No. 3 September 2004 Journal of Pain and Symptom Management 277 Clinical Note The Effect of Transdermal Fentanyl Treatment on Serum Cortis...

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Vol. 28 No. 3 September 2004

Journal of Pain and Symptom Management


Clinical Note

The Effect of Transdermal Fentanyl Treatment on Serum Cortisol Concentrations in Patients with Non-Cancer Pain Emine Ozyuvaci, MD, Nergis Yanmaz Alnigenis, MD, and Aysel Altan, MD Department of Anesthesiology and Intensive Care (E.O., A.A.), and Department of Internal Medicine, Division of Rheumatology (N.Y.A), SSK Okmeydani Educational Hospital, Istanbul, Turkey

Abstract We treated 50 patients with chronic nonmalignant pain using transdermal fentanyl (TDF) 25 mg/hr and concurrently measured pain using a visual analog scale (VAS) and serum cortisol concentration. We determined these outcomes at baseline and on days 30, 60, and 90 of the therapy. The patients also were asked to document any adverse effects. We found that mean cortisol concentrations on days 30, 60, and 90 of therapy were significantly (P ⬍ 0.0001) lower than the basal mean cortisol level, and mean VAS scores at days 30, 60, and 90 of therapy were also significantly better than the initial mean value (P ⬍ 0.0001). Fourteen patients experienced severe adverse events. These observations suggest that serum cortisol concentrations may be elevated in chronic non-cancer pain states and that TDF therapy can reduce cortisol levels in parallel with reduction in pain. J Pain Symptom Manage 2004;28:277–281. 쑖 2004 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Transdermal fentanyl, chronic pain, serum cortisol concentration

Introduction Opioid analgesics are effective therapies for cancer-related pain and they are widely used.1 The World Health Organization (WHO) recommended a “ladder” approach for cancer pain

Presented in part at the European Federation of the International Association for the Study of Pain Chapters conference, “Pain in Europe IV,” Prague, Czech Republic, September 2–6, 2003. Address reprint requests to: Emine Ozyuvaci, MD, Yesil Belgrad Evleri, B-12 34077, Gokturk Beldesi, Kemerburgaz-Istanbul, Turkey. Accepted for publication: November 10, 2003.

쑖 2004 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.

treatment in 1990, in which opioid analgesics are given at the second and the third level of pain severity.2 There also has been an increasing interest in using opioids for non-cancer pain, basically using the same approach recommended by WHO.3 But the potential for toxicity, adverse effects, and abuse has been a great source of concern for both patients and physicians in using these medications for non-cancer pain.4 A variety of opioids has been used for both cancer and non-cancer pain. Transdermal fentanyl (TDF) has been found to be effective in the treatment of non-cancer pain in several controlled studies, including in patients with neuropathic pain.5–7 0885-3924/04/$–see front matter doi:10.1016/j.jpainsymman.2003.11.004


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In acute pain, serum cortisol concentration may increase as a reaction to stress. In conditions with chronic non-cancer pain, the hypothalamic-pituitary-adrenal axis (HPA) is activated and serum cortisol concentration may increase, as in acute pain.8 In this study, we investigated the efficacy of TDF for non-cancer pain, measured the serum cortisol levels and searched for any effects of TDF on serum cortisol concentrations in patients with non-cancer pain.

Methods The study was conducted by the Department of Anesthesiology, Division of Pain, and the Department of Internal Medicine, Division of Rheumatology, at the Okmeydani SSK Educational Hospital. We studied patients referred to the Pain Clinic and Rheumatology Outpatient Clinics. The study was approved by the local ethics committee and the patients gave informed consent. The patients were included in the study according to the following inclusion and exclusion criteria. Inclusion criteria: 1) age between 20 to 60; 2) either sex; 3) patients with regional or widespread pain for more than 2 years, related to rheumatoid arthritis, osteoarthritis, fibromyalgia syndrome, chronic low back pain, osteoporosis, or failed back; 4) unresponsive or inadequately responsive to standard therapeutic modalities for pain at the time of the study; 5) score on a 0–10 cm visual analog scale (VAS) for pain intensity ⬎6 cm; and 6) no use of opioids or opioid derivatives before. Exclusion criteria: 1) history of allergy or hypersensitivity to opioids; 2) presence of a skin disease; 3) current or past corticosteroid treatment; 4) reduced level of consciousness or inability to give informed consent; 5) pregnancy, lactation, or possibility of pregnancy; 6) concomitant psychiatric disorders; 7) history of substance abuse; 8) history of cardiac, nervous system, and respiratory disease; 9) patients with occupations that make the use of this kind of medication (opioids) risky; and 10) use of sedatives, hypnotics, phenothiazines, muscle relaxants, or antihistaminics with sedative properties. At the initial evaluation, medical history was obtained and a full physical examination was done. We classified pain according to the International Association for the Study of Pain

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(IASP) system, which defines localization, system, temporal characteristics, intensity, and etiology. We measured baseline serum cortisol concentrations before starting therapy. Blood samples were taken at 8 am after an overnight fast. Samples were measured by the same university reference laboratory for each patient. Normal values for serum cortisol concentration were 5 to 25 µg/dL. At baseline, we evaluated pain severity by using a VAS, after which pain treatment was initiated with TDF, 25 µg/hr, patch changed every 72 hours. Treatment was to be continued for three months. After starting therapy with TDF, we measured serum cortisol concentrations on Days 30, 60, and 90 at 8 am, and evaluated pain concurrently using the VAS. We also questioned the patients for any adverse effects. Patients were asked to call the investigator if they experienced any disturbing symptoms and/or any adverse effects like nausea and vomiting, sweating, constipation, dizziness, hypotension, or somnolence. Patients who could not tolerate the medication were dropped from the study. The statistical analysis was performed using GraphPad Prisma V.3 statistical software. Continuous variables, expressed as means and standard deviations, were compared using the Friedman test and posthoc Dunn’s multiple comparison tests. A P-value less than 0.05 was regarded as significant.

Results Fifty patients fulfilled the criteria above and gave informed consent. In the first 24 hours of TDF therapy, 14 patients (28%) experienced severe adverse effects and therapy was stopped. Ten (20%) of these patients had severe nausea and vomiting, and 4 patients (8%) had severe confusion. No adverse effects were seen in the remaining 36 patients. The baseline characteristics and pain durations of the remaining 36 patients are shown in Table 1. Patients’ serum cortisol concentrations at baseline and on Days 30, 60, and 90 of the therapy are shown in Figure 1. Initial mean serum cortisol concentration was 17.77 ⫾ 2.82 µg/dL. On Day 30, mean concentration was 13.42 ⫾ 2.85 µg/dL, on Day 60 it was 10.79 ⫾

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Transdermal Fentanyl and Serum Cortisol

Table 1 Baseline Characteristics of Study Patients and Pain Classification Sex (F/M) Age (years), mean ⫾ SD Duration of chronic pain in months, mean ⫾ SD Pain type n(%) Neuropathic pain Nociceptive pain Combined (neuropathic and nociceptive) IASP classification of (most common) pain, n(%) Axis I: region Lower back Lower limbs Axis II: system Nervous system Musculoskeletal or connective tissue Axis III: temporal characteristics Continuous, fluctuating severity Continuous, non-fluctuating severity Axis IV: intensity: onset time since Severe (⬎6 months) Medium (⬎6 months) Axis V: etiology, n(%) Degenerative or mechanical Trauma, operation or burns


8 (22) 22 (61)

30 and Day 60, on Day 30 and Day 90, and on Day 60 and Day 90 were significant (P ⬍ 0.0001). The initial mean VAS score was 9.28 ⫾ 0.91 cm. On Day 30 of the treatment, mean VAS score was 5.61 ⫾ 1.25 cm. On Day 60, it was 4.33 ⫾ 1.17 cm, and on Day 90, it was 1.83 ⫾ 1.80 cm. The VAS scores decreased during therapy, and this was statistically significant (P ⬍ 0.0001). The difference between initial mean VAS score and the mean VAS scores at Days 30, 60, and 90 of therapy were significant (P ⬍ 0.0001). The differences between mean VAS scores at Day 30 and Day 60, at Day 30 and Day 90, and at Day 60 and Day 90 were significant (P ⬍ 0.0001) (Fig. 2).

31 (86) 2 (6)


28/8 47.75 ⫾ 11.85 50.25 ⫾ 17.58 12 (33) 10 (28) 14 (39)

20 (56) 4 (11)

24 (66) 12 (34) 18 (50) 9 (25)

2.33 µg/dL, and on Day 90 it was 8.57 ⫾ 2.49 µg/dL. Serum cortisol concentrations showed a statistically significant decrease during therapy (P ⬍ 0.0001). The differences between baseline mean cortisol level and the mean cortisol concentrations on Days 30, 60 and 90 of therapy were also significant (P ⬍ 0.0001). The differences between the mean cortisol levels on Day

Pain is subjective and there is no objective method to measure it. Measurement of hormones released by the neuroendocrine system due to pain may provide an objective correlate of pain reduction in response to therapy. In several studies, the efficacy of pain medications has been evaluated by measuring abnormalities in the concentrations of adrenocorticotropic hormone (ACTH), dehydroepiandrosterone (DHEA), androstenedione (AND), or serum cortisol concentration.9 In the present study, we evaluated the effect of TDF on cortisol levels in patients with noncancer pain and studied the correlation between cortisol concentrations and pain severity.

Fig. 1. Basal cortisol concentrations (µg/dL) and the levels on Days 30, 60, and 90 of pain treatment.


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Fig. 2. Initial VAS scores of the patients and the scores on Days 30, 60 and 90 of pain treatment.

Contrary to previous reports, all of our patients had normal baseline cortisol levels. Nonetheless, these levels may actually be increased from a lower baseline level. During the course of the study, serum cortisol levels decreased gradually with therapy. In a preliminary study on chronic pain and cortisol concentrations in a group of patients with diagnoses different than our patients, Tennant et al. found abnormal serum cortisol concentrations in 26 of 40 patients with chronic pain;8 there were only 14 patients with normal cortisol concentrations. TDF, methadone, and modified-release oxycodone were used as longacting agents and there was a significant decrease in cortisol levels following therapy.8 The authors concluded that serum cortisol concentrations may be an objective pain marker to follow the response to pain therapy. In our study, we studied the correlation between serum cortisol levels (the proposed biologic marker) and pain in more detail. During 3 months of TDF therapy, we measured cortisol levels and VAS scores every month. We did not find the high baseline cortisol levels noted in Tennant et al.’s study. All of our patients’ baseline cortisol levels were within normal limits. But during therapy, cortisol concentrations gradually decreased and we determined a parallel decrease in VAS scores. Tennant et al., as an explanation for high cortisol levels in their 12 patients, said that stress stimulates HPA and thus increases serum cortisol concentrations.8 The association between stress and high cortisol levels also has been

shown in other studies.10,11 Severe pain and stress may occur together and cause an increase in cortisol levels.12 We did not question our patients about their stress and depression levels and future studies of pain response and hormone levels should separately assess these phenomena. In the present study, like many controlled studies,1,3,6,13,14 we found that TDF can be an effective therapy for non-cancer pain. In a previous study of 48 patients with neuropathic pain, significant pain relief was observed after the first dose of TDF.6 In our population, however, a large proportion of patients had severe adverse effects at the beginning of therapy and stopped treatment. Other studies have recorded side effects in as many as one-third of patients.13 These observations suggest that the dose used in this study, the smallest now available (25 µg/hr), may be relatively too high for some opioid-naive patients. In conclusion, serum cortisol concentration may be an objective marker for following the effect of opioid therapy. Further studies are needed to evaluate the usefulness of cortisol and other serologic markers in following therapy with different opioids and in varied populations.

Acknowledgments This study was supported by the Janssen Pharmaceutical Research Foundation in Turkey.

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References 1. Milligan K, Minet ML, Borchert K, et al. Evaluation of long-term efficacy and safety of transdermal fentanyl in the treatment of chronic non-cancer pain. J Pain 2001;2(4):197–204. 2. World Health Organization. Cancer pain relief and palliative care: report of a WHO expert committee. World Health Organization Technical Reports series (second edition). Geneva: World Health Organization, 1996. 3. Allan L, Hays H, Jensen NH, et al. Randomized crossover trial of transdermal fentanyl and sustained-release oral morphine for treating chronic non-cancer pain. BMJ 2001;322:1154–1158. 4. Portenoy RK. Chronic opioid therapy in nonmalignant pain. J Pain Symptom Manage 1990; 5(Suppl):546–562. 5. Jeal W, Benfield P. Transdermal fentanyl: a review of its pharmacological properties and therapeutic efficacy in pain control. Drugs 1997;53: 109–138. 6. Dellemijn PL, Van Duijn H, Vanneste JAL. Prolonged treatment with transdermal fentanyl in neuropathic pain. J Pain Symptom Manage 1998;16: 220–229.


7. McQuay HJ. Opioids in chronic pain. Br J Anaesth 1989;63:213–226. 8. Tennant F, Hermann L. Normalization of serum cortisol concentration with opioid treatment of severe chronic pain. Pain Medicine 2002;3(2):132– 134. 9. Pacheco MJB, Amado JA, Hoyos ML, et al. Hypothalamic-pituitary-adrenocortical axis function in patients with polymyalgia rheumatica and giant cell arteritis. Semin Arthritis and Rheum 2003;32(4): 266–272. 10. Axelrod J, Reisine TD. Stress hormones: their interaction and regulation. Science 1984;224:452– 459. 11. Theorell T. Stress syndromes. Ann Clin Res 1984;19:53–61. 12. Ferraccioli G, Cavalieri F, Salaffi F, et al. Neuroendocrinologic findings in primary fibromyalgia (soft tissue chronic pain syndrome) and in other chronic rheumatic conditions (rheumatoid arthritis, low back pain). J Rheumatol 1990;17(7):869–873. 13. Dellemijn PL. Opioids in non-cancer pain: a lifetime sentence. Eur J Pain 2001;5:333–339. 14. Simpson RK, Edmondson EA, Constant CF, Collier C. Transdermal fentanyl as treatment for chronic low back pain. J Pain Symptom Manage 1997;4: 218–224.