The Pain Pen for Breakthrough Cancer Pain: A Promising Treatment

Vol. 29 No. 2 February 2005 Journal of Pain and Symptom Management 213 Clinical Note The Pain Pen for Breakthrough Cancer Pain: A Promising Treatment Roelien H. Enting, MD, Carlo Mucchiano, MD, Wendy H. Oldenmenger, MSc, Magdalena Fritzon, RN, Anna Wallen, RN, Simone Goslinga-van der Gaag, RN, Peter A.E. Sillevis Smitt, MD, and Elmar Delhaas, MD Daniel den Hoed Cancer Center (R.H.E., W.H.O., P.A.E.S.S.), Erasmus Medical Center, and Medical Center Rijnmond-Zuid (S.G.G., E.D.), Rotterdam, The Netherlands; and Höglands Hospital (C.M., M.F., A.W.), Eksjö, Sweden Abstract Breakthrough pain has been recognized as a challenging pain phenomenon in cancer. Oral transmucosal fentanyl citrate (OTFC) recently has been recommended as treatment, but OTFC is not widely available. Therefore, alternatives are needed. In two separate pilot studies, 58 patients were instructed to self-administer subcutaneous (SC) rescue opioids (hydromorphone (n 43), morphine (n 11), or sufentanil (n 4), using a standard injection-pen for breakthrough pain. Patients were asked to rate the overall efficacy of SC rescue opioids on a 3-point scale (not noticeable, moderate, or good). The efficacy was rated as good in 49 patients (84%, 95% CI: 73-91%), moderate in 8 patients (14%), and not noticeable in 1 patient (2%). The median dose per injection was equianalgesic to 25 mg of SC morphine (range: 4-150 mg). Twenty-nine patients (50%) were treated until death (n 26) or were on ongoing treatment (n 3). Patients were treated for a median of 6 weeks (1 day 41 months). J Pain Symptom Manage 2005;29:213 217. 2005 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Breakthrough pain, cancer, opioids, rescue doses, parenteral opioids, injection pen Introduction Since the early 1990s, breakthrough pain has been recognized as a challenging pain phenomenon in cancer. At least two-thirds of patients with advanced cancer report pain. Pain is typically experienced most of the time and is usually managed with a fixed-schedule opioid regimen. 1 In addition to some degree of persistent pain, 40-80% of patients also has transient increases in baseline pain. 2 Oral transmucosal fentanyl citrate (OTFC) (Actiq ) has been recommended for breakthrough pain. 3 However, OTFC is not available in many countries, including The Netherlands. Therefore, alternative treatment options are needed. We report the combined results of two pilot studies evaluating subcutaneous (SC) administration of rescue opioids for breakthrough pain. Address reprint requests to: Roelien H. Enting, MD, Department of Neurology, P.O. Box 30001, 9700 RB Groningen, The Netherlands. Accepted for publication: May 8, 2004. 2005 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. Methods Two research groups, one in The Netherlands (two centers) and another in Sweden (one 0885-3924/05/$ see front matter doi:10.1016/j.jpainsymman.2004.05.010

214 Enting et al. Vol. 29 No. 2 February 2005 center), performed an open-label pilot study with self-administration of SC opioid injections for breakthrough pain in cancer. The preliminary results have been published before. 4,5 Adult inpatients or outpatients with cancerrelated breakthrough pain while using fixedschedule opioids were eligible for the studies. Because of the exploratory nature of the study, no further entry criteria were defined. Patients were instructed by a pain nurse to self-administer rescue opioids for any pain flare using a standard injection pen (Disetronic Medical Systems AG, Burgdorf, Switzerland). The injection pen is a standard delivery device for easy and accurate subcutaneous drug delivery. The system is widely used for insulin treatment. The smallest volume is 50 µl, which is the equivalent of one click. For larger volumes, the dosage knob is turned clockwise until the desired number of clicks appears. The total amount of drug is then injected by pressing the dosage knob once. Dosage accuracy is in accordance with ISO/DIS 11608. A very thin needle (25 G or smaller) is used for injection. Glass 3.15 ml ampoules were filled with hydromorphone, morphine, or sufentanil. The starting dose was 10 15% of the total daily dose. In the Swedish center, all patients were treated with SC hydromorphone (hydromorphone 20 mg/ml or 40 mg/ml. In the Dutch centers, three different opioids were used (hydromorphone 10 mg/ml, sufentanil 50 µg/ml, or morphine 40 mg/ml). Rescue opioid doses were titrated depending on efficacy and side effects pursuant to instructions of the pain nurse. During the titration phase, the pain nurse contacted the patient by phone every weekday. The following demographic and medical variables were collected for all patients: gender, age, type of cancer, tumor status (no evidence of disease, stable disease, or progressive disease), current anti-tumor treatment, number of breakthrough pain episodes per day, cause of pain (nociceptive, neuropathic, or mixed), fixed schedule opioids (type of opioid, route, and dose), and prior rescue medication. Opioid dose was converted to oral or SC morphine equivalent doses using published analgesic tables. 6,7 Patients were asked to rate the overall efficacy of SC rescue opioids on a 3-point scale (not noticeable, moderate, or good). The number of patients who discontinued the treatment due to side effects was noted. Patients could opt for either spinal analgesia or intravenous or subcutaneous patient-controlled analgesia (PCA) when the pain pen was no longer effective. The duration of treatment and the reason for discontinuation were assessed for all patients. Medians are reported with their ranges. Proportions are reported with their 95% confidence intervals (95% CIs), as appropriate. The Mann-Whitney U test was used to compare durations of treatment. Correlations were tested with Spearman s rank correlation test. Reported P values are two-tailed and were considered significant at P 0.05 level. Results A total of 58 patients participated in the pilot studies (Sweden: n 40; The Netherlands: n =18) and were treated between April 1999 and December 2001. The sociodemographic and baseline treatment variables are given in Tables 1 and 2. Patients were treated with SC hydromorphone (n 43), SC morphine (n 11) or SC sufentanil (n 4). The median equianalgesic dose per injection was 25 mg of SC morphine (equianalgesic to 5 mg of SC hydromorphone), the range was 4 150 mg SC morphine. A significant correlation was found between rescue dose and fixed schedule opioids (r 0.6, P 0.01) (Figure 1). The highest Table 1 Sociodemographic Variable of 58 Patients Treated with SC Opioids for Breakthrough Pain n % Male gender 24 41 Age (median, range) 60 yr (33 87 yr) Cancer status progressive disease 58 100 Cancer type Gastrointestinal 27 47 Breast 8 14 Urological 7 12 Gynecological 6 10 Lung 3 5 Head and Neck 3 5 Other 4 7 Current cancer treatment Chemotherapy 9 16 Radiotherapy 5 9 None 44 76 Type of pain Nociceptive 11 19 Mixed 46 79 No. of BKP episodes/day (median, range) 3 (0 24); SC subcutaneous; BKP breakthrough pain.

Vol. 29 No. 2 February 2005 Pain Pen for Breakthrough Cancer Pain 215 Table 2 Baseline Treatment Variables of 58 Patients Treated with SC Opioids for Breakthrough Pain n % NSAIDs 16 28 Fixed-schedule opioids Fentanyl patch a 51 88 Morphine 3 5 Methadone 1 2 Oxycodone 3 5 Intrathecal morphine 1 2 Oral equianalgesic dose/24 hrs (median, range) 280 mg (30 1920 mg) Route of prior rescue opioids Oral 41 71 Parenteral 17 29 Type of prior rescue opioid Morphine 37 64 Fentanyl 2 3 Ketobemidon 10 17 Hydromorphone 2 3 Oxycodone 7 12 NSAIDs nonsteroidal anti-inflammatory drugs; SC subcutaneous. a One patient had both a fentanyl patch and oxycodone. volume delivered per injection was 0.65 ml. The overall efficacy was rated as good in 49 patients (84%, 95% CI: 73-91%), moderate in 8 patients (14%), and not noticeable in one patient (2%). There were no significant differences between the three different opioids, but numbers are small (data not shown). One patient (2%) discontinued treatment due to side effects; the efficacy in this case was rated as good. The median duration of treatment was 6 weeks (range: 1 day 41 months), and was not significantly different for patients treated until death compared to patients who discontinued using the pain pen. Twenty-six patients (45%) were treated until death, three patients (5%) were still treated with the pain pen by the end of the study after 28, 29, and 41 months, and 2 patients (3%) had no more breakthrough pain. Twenty-seven patients (47%, 95% CI: 35-60%) discontinued using the pain pen and were subsequently treated with PCA (n 18 [31%]}, spinal analgesia (n 8 [14%]), or oral opioids (n 1 [2%]). Although time to onset of effect was not formally measured, patients noticed the first effect 5 to 10 minutes after administration of the SC opioids. Discussion The incidence of breakthrough pain has been found to vary widely between 40% to more than 80% of patients, depending on the definitions used and the clinical setting. 2 U.S. investigators have argued that breakthrough pain can only be assessed after baseline pain is properly controlled with fixed schedule opioids, whereas European investigators consider any acute transient pain with an intensity that flares over baseline pain as breakthrough pain. Fig. 1. Rescue opioid dose in relation to initial dose of fixed schedule opioids (n 54).

216 Enting et al. Vol. 29 No. 2 February 2005 Treatment poses several difficulties. The first problem is the slow onset of pain relief following oral treatment with immediate-release (IR) opioids: a typical pain flare lasts up to 30 minutes, whereas the time to peak effect of oral IR opioids is approximately 60 minutes. The second problem is that preemptive treatment is feasible in only those 30% of episodes that are predictable. 2,9,10 OTFC was the first analgesic specifically investigated for the control of breakthrough pain and was found to be superior to IR morphine. 11 The transmucosal route has been further explored in anecdotal reports and pilot studies using intranasal or sublingual administration of fentanyl or sufentanil. 12 15 These preparations were well tolerated and effective, but only small doses can be given in this way. Intranasal administration is limited to approximately 0.2 ml, and the maximum sublingual volume is 3 ml (150 µg) for fentanyl and 0.5 ml (25 µg) for sufentanil. 12 15 The equianalgesic dose of 800 µg OTFC was found to be 10 mg intravenous (IV) morphine. 16 By extrapolation, 25 µg sublingual sufentanil which is ten times more potent than fentanyl is estimated to be equivalent to approximately 3 mg IV morphine. Thus, it appears that sublingual administration of opioids also is limited to relatively low doses. One of the advantages of the injection pen is that much higher doses can be given. In our study, the highest dose given was 30 mg SC hydromorphone per injection. Another advantage is that the injection pen may be applicable in patients with mucositis. A third advantage is cost; the average monthly cost is approximately 600 euros ($732) for patients who treat 2 episodes of breakthrough pain per day. The pain pen costs 122 euros ($148) each, and the average monthly cost is 100 euros ($122). As expected, but contrary to findings for OTFC, a correlation was found between the doses of the fixed schedule opioids and rescue opioids. 11 When oral rescue opioids fail, patients may be treated with SC (or IV) PCA with a continuous infusion and bolus doses as supplementary analgesia to counter breakthrough pain. 2,17 At the time of this study, little was known about the acceptability of different routes of analgesia for breakthrough pain, but recently it was found that subcutaneous analgesia was considered acceptable for mild to moderate breakthrough pain in 52% of patients, and for severe breakthrough pain in 87% of patients. 18 In conclusion, our study shows that an alternative is available for patients with breakthrough pain that is difficult to manage. It was demonstrated that SC administration of opioids with an injection pen is feasible following instructions and is effective. The overall efficacy was rated as good in 49 patients (84%). We have now started a randomized controlled crossover study in 50 patients comparing oral IR morphine and self-administration of SC hydromorphone using an injection pen. Hydromorphone was preferred to morphine because its higher potency is ideal for low-volume injections. Sufentanil was not chosen because of concerns about the stability of sufentanil in the ampoules. 19 Time of onset of pain relief will be measured by a stopwatch, and will be one of the major endpoints of the trial. Acknowledgments The authors wish to express their gratitude to Sander C.G Bos (Disetronic Medical Systems BV, Vianen, The Netherlands), and Göran Sällström (Disetronic Medical Systems AG, Burgdorf, Switzerland) for the supply of the injection pens, and to Paul J.J.M. Janssen, pharmacist in the Daniel den Hoed Cancer Center, Erasmus Medical Center, Rotterdam, The Netherlands, for the supply of hydromorphone for the Dutch patients. The Dutch portion of the study was supported by a grant from the Pain Expertise Center of the Erasmus Medical Center in Rotterdam, The Netherlands. References 1. World Health Organization. Cancer pain relief and palliative care. Report of a WHO expert committee. Geneva: World Health Organization, 1990. 2. Mercadante S, Radbruch L, Caraceni A, et al. Episodic (breakthrough) pain: consensus conference of an expert working group of the European Association for Palliative Care. Cancer 2002;94: 832 839. 3. Hanks GW, de Conno F, Cherny N, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer 2001;84:587 593. 4. Delhaas E, Savage C, Sillevis Smitt P, et al. Preliminary results of the pain pen: a breakthrough for

Vol. 29 No. 2 February 2005 Pain Pen for Breakthrough Cancer Pain 217 breakthrough pain? [Abstract]Proceedings of the 7th Congress of the European Association for Palliative Care. Palermo, Italy, 2001. 5. Mucchiano C, Fritzon M, Wallen A. Self-administration of SC hydromorphone with D-pen for breakthrough pain during opioid medication with Duragesic patch. [Abstract] Proceedings of the 7th Congress of the European Association for Palliative Care. Palermo, Italy, 2001. 6. Portenoy RK, Lesage P. Management of cancer pain. Lancet 1999;353:1695 1700. 7. Breitbart W, Chandler S, Eagel B, et al. An alternative algorithm for dosing transdermal fentanyl for cancer-related pain. Oncology 2000;14:695 717. 8. Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain 1990; 41:273 281. 9. Portenoy RK, Payne R, Jacobsen P. Breakthrough pain: characteristics and impact in patients with cancer pain. Pain 1999;81:129 134. 10. Gomez-Batiste X, Madrid F, Moreno F, et al. Breakthrough cancer pain: Prevalence and characteristics in patients in Catalonia, Spain. J Pain Symptom Manage 2002;24:45 52. 11. Coluzzi PH, Schwartzberg L, Conroy JD, et al. Breakthrough cancer pain: A randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain 2001;91:123 130. 12. Zeppetella G. An assessment of the safety, efficacy, and acceptability of intranasal fentanyl citrate in the management of cancer-related breakthrough pain: A pilot study. J Pain Symptom Manage 2000; 20:253 258. 13. Kunz KM, Theisen JA, Schroeder ME. Severe episodic pain: Management with sublingual sufentanil. J Pain Symptom Manage 1993;9:189 190. 14. Zeppetella G. Sublingual fentanyl citrate for cancer-related breakthrough pain: A pilot study. Palliat Med 2001;15:323 328. 15. Jackson K, Ashby M, Keech J. Pilot dose finding study of intranasal sufentanil for breakthrough and incident cancer-associated pain. J Pain Symptom Manage 2002;23:450 452. 16. Lichtor JL, Sevarino FB, Joshi GP, et al. The relative potency of oral transmucosal fentanyl citrate compared with intravenous morphine in the treatment of moderate to severe postoperative pain. Anesth Analg 1999;89:732 738. 17. Caraceni A, Brunelli C, Galbiati A, et al. Role and limits of morphine PCA infusions for the treatment of breakthrough pain in cancer: Preliminary results. [Abstract] Proceedings of the 7th Congress of the European Association for Palliative Care. Palermo, Italy, 2001. 18. Walker G, Wilcock A, Manderson C, et al. The acceptability of different routes of administration of analgesia for breakthrough pain. Palliat Med 2003; 17:219 221. 19. Roos PJ, Glerum JH, Meilink JH. Stability of sufentanil citrate in a portable pump reservoir, a glass container, and a polyethylene container. Pharm Weekly Sci 1992;14:196 200.