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Pilot Study of Nasal Morphine-Chitosan for the Relief of Breakthrough Pain in Patients With Cancer
598
Journal of Pain and Symptom Management
Vol. 24 No. 6 December 2002
Clinical Note
Pilot Study of Nasal Morphine-Chitosan for the Relief of Breakthrough Pain in Patients With Cancer Hilary Pavis, MA, MRCGP, Andrew Wilcock, DM, FRCP, Jane Edgecombe, MRCP, Diane Carr, RGN, Cathann Manderson, RGN, Ann Church, PhD, and Anthony Fisher, PhD Hayward House Macmillan Specialist Palliative Care Unit (H.P., A.W., J.E., D.C., C.M.), Nottingham City Hospital NHS Trust, and West Pharmaceutical Services (A.C., A.F.), Albert Einstein Center, Nottingham Science and Technology Park, Nottingham, United Kingdom
Abstract Breakthrough pain in patients with cancer is common, often unpredictable, and can rapidly become severe. Treatment using the oral administration of opioids is not optimal due to the slow onset of pain relief. Nasal administration of analgesics potentially offers more rapid pain relief. This study investigates the tolerability and efficacy of a novel morphine-chitosan formulation. Twenty episodes of breakthrough pain were observed in 14 patients with cancer who received 5–80 mg of nasal morphine-chitosan. Nasal symptoms, sedation, giddiness, nausea, and other volunteered symptoms, along with pain scores (pain intensity and pain relief), were recorded at baseline and at regular intervals up to 4 hours after administration, together with an overall satisfaction rating. The formulation was acceptable to patients, generally well tolerated, and had an onset of pain relief 5 minutes after dosing. This formulation warrants further study. J Pain Symptom Manage 2002;24:598–602. © U.S. Cancer Pain Relief Committee, 2002. Key Words Cancer, pain, breakthrough pain, morphine, nasal drugs
Introduction Morphine, given regularly by mouth, is commonly recommended for the relief of cancer pain.1 Breakthrough pain, a transitory exacerbation of pain in a patient who has mainly stable and adequately controlled pain, is generally treated with an additional dose of immediate-
Address reprint requests to: Andrew Wilcock, DM, FRCP, Hayward House Macmillan Specialist Palliative Care Unit, Nottingham City Hospital NHS Trust, Hucknall Road, Nottingham NG5 1PB, United Kingdom. Accepted for publication: January 19, 2002. © U.S. Cancer Pain Relief Committee, 2002 Published by Elsevier, New York, New York
release morphine, administered orally as a solution or tablet. Onset of pain relief may take 20– 30 minutes and peak analgesia one hour or more, in keeping with a mean (range) time to maximum plasma concentration of 1.1 (0.2– 3.5) hours.2,3 Parenteral administration provides a more rapid onset of pain relief, but is not always an available, convenient, or preferred option. Thus, other non-oral routes of administration, such as transmucosal, nasal, or pulmonary, that may provide convenient and rapid pain relief are worth pursuing.4 The nasal route of administration is potentially the most convenient alternative method for drug delivery. Nasal drug absorption is 0885-3924/02/$–see front matter PII S0885-3924(02)00522-5
Vol. 24 No. 6 December 2002
Nasal Morphine-Chitosan for Breakthrough Pain
aided by a highly vascular epithelium, a large surface area and the avoidance of first pass metabolism. Morphine however, being hydrophilic, is poorly absorbed nasally. This problem may be overcome by combining morphine with chitosan, a bio-adhesive material that slows the mucociliary clearance of morphine, allowing more time for absorption.5,6 In healthy volunteers, nasal morphine-chitosan is well tolerated, and has mean values for bioavailability, time to peak plasma concentration and elimination half-life of 56%, 15 minutes, and 3 hours, respectively.7 In this pilot study, we have examined, for the first time, the tolerability and efficacy of a nasal morphine-chitosan solution in patients.
Methods Subjects were inpatients at a specialist palliative care unit. All had cancer-related pain treated with regularly scheduled opioid administration and all experienced episodes of breakthrough pain, for which they used and found effective, additional doses of oral morphine. Episodes of breakthrough pain treated with nasal morphine-chitosan were of at least of moderate severity (i.e., 2 on the pain scale) and occurred more than one hour after any immediate-release morphine preparation. All regularly prescribed analgesics were continued. A maximum of two episodes was observed per patient. Patients were excluded if too frail or unwell to participate, psychological distress significantly contributed to their pain, or if their nasal passages were abnormal, congested, or occluded. Nasal morphine was administered by research staff in a standardized way using the same dose that the patient received orally for episodes of breakthrough pain. Two preparations of morphine-chitosan were supplied, 5 mg/0.1 ml and 20 mg/0.1 ml; this allowed morphine doses in the range of 5–80mg to be administered in 1–4 sprays from Pfeiffer single 0.1ml unit dosing devices (maximum of two sprays per nostril). Nasal symptoms (sore, itching or stinging nose, sore or stinging throat, dry or stuffy nose, runny nose, or taste disturbance), sedation, giddiness, nausea and other volunteered symptoms, along with pain scores (pain intensity and pain relief), were recorded at baseline and
599
at regular intervals up to 4 hours after administration. Nasal symptoms, sedation, giddiness, nausea, and other symptoms were assessed on a scale of 0–4, where 0 represents ‘none’ and 4 ‘very severe’. Pain intensity was recorded on a scale of 0–4, where 0 represents ‘no pain’ and 4 ‘very severe’ pain. Pain relief was assessed on a scale of 4 to 4, where 4 represents ‘complete relief’ and 4 ‘pain has become maximal’. At the end of the study, patients were asked to provide an overall satisfaction rating of excellent, very good, good, fair, or poor. All patients gave written informed consent and the study was approved by Nottingham City Hospital Research Ethics Committee.
Results Twenty episodes of pain were observed in 14 patients. There were 9 men and 5 women. The mean (range) age and World Health Organization performance status were 66 (44–79) years and 2.4 (1–3), respectively. In accordance with their usual dose of oral morphine for breakthrough pain, patients received one or two doses of 5 mg (3 patients), 10 mg (3 patients), 15 mg (2 patients), 20 mg (4 patients), 30 mg (1 patient) or 80 mg (1 patient) of nasal morphine.
Overall Satisfaction Patients rated the 20 episodes with nasal morphine-chitosan as ‘excellent’ (1), ‘very good’ (6), ‘good’ (11) and ‘fair’ (2).
Tolerability The majority of nasal symptoms were rated as 0 ‘none’ or 1 ‘slight,’ and were transient in nature (Table 1). ‘Severe’ taste disturbance was reported in 4 episodes and appeared dose related. This occurred 5 minutes after dose administration in 3 patients, who described it as a bitter taste; in the fourth patient, it was reported prior to drug administration and remained unchanged throughout the study. The most frequent non-nasal adverse effect was sedation, reported at some point during 16 episodes. In 8 episodes, it appeared temporally related to the nasal morphine and, at its worst, patients rated it as ‘very severe’ (1), ‘moderate’ (2) or ‘mild’ (5). During two episodes, sedation that was reported at baseline subsequently worsened following treatment. Baseline seda-
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Vol. 24 No. 6 December 2002
Table 1 Incidence (%) of Each Assessment Score and the Number of Episodes of Breakthrough Pain Recording that Score No. of Episodes with a Score of:
Incidence (%) of Score Variable Sore/stinging nose Dry/stuffy nose Runny nose Sore/stinging throat Taste disturbance Nausea Sedation Giddiness Other symptomsa
0 none
1 slight
2 moderate
3 severe
4 very severe
0
1
2
3
4
149 (83) 150 (83) 158 (88) 149 (83) 121 (67) 158 (88) 101 (56) 158 (88) 4 (16)
24 (13) 21 (12) 19 (11) 24 (13) 36 (20) 18 (10) 47 (26) 18 (10) 11 (44)
6 (3) 9 (5) 3 (2) 6 (3) 12 (7) 4 (2) 26 (14) 2 (1) 6 (24)
1 (1) 0 (0) 0 (0) 1 (1) 11 (6) 0 (0) 5 (3) 2 (1) 1 (4)
0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 3 (12)
20 20 20 20 20 20 20 20 3
11 6 6 9 13 7 16 7 4
5 1 2 5 7 2 9 1 4
1 0 0 1 4 0 4 1 1
0 0 0 0 0 0 1 0 1
The total number of assessments for each variable was 180 (20 episodes 9 assessments). aOther symptoms (dry mouth/throat, light headedness, muscle aches) were recorded in 5 episodes (25 assessment scores in total).
tion improved or stayed unchanged following treatment in two episodes each (Table 2). One patient reported a ‘very severe’ dry mouth. This was present prior to administration, persisted over the first 15 minutes after dosing, and subsequently improved to ‘slight’ over the duration of the study.
Discussion Breakthrough pain in patients with cancer is common, often unpredictable and can be severe.8,9 Morphine given orally, although commonly used, is not optimal due to the slow onset of pain relief. Parenteral administration provides a more rapid onset of pain relief, but is not always available or convenient. Exploration of other routes of analgesic administration for the treatment of breakthrough pain has seen the development of the oral transmucosal fentanyl citrate lozenge, which provides more rapid onset pain relief than oral morphine.10,11 This formulation has some limitations; the effective dose for a patient is difficult to predict and requires dose titration, it is unsuitable in approximately 25% of patients, and is expensive. We, like others, have explored the delivery of strong opioids nasally.12–14 The nose has a large surface area due to microvilli on the epithelial surface and is highly vascularized. These
Efficacy Improvements in pain intensity and relief were reported at 5 minutes and reached a maximum after 45 minutes, at which time pain intensity was rated as ‘slight’ and pain relief as ‘eased moderately’. In 9 episodes, patients received a dose of a regularly prescribed analgesic 1–4 hours after nasal morphine-chitosan. Mean pain intensity and relief scores for the first hour following administration of nasal morphine are therefore presented, as no additional regular analgesic was administered during this period (Figure 1).
Table 2 Assessment Scores of Sedation Following Nasal Morphine-Chitosan Episode number Time (min)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
0 5 15 30 45 60 120 180 240
2 3 4 2 1 2 2 2 2
0 0 0 0 0 0 0 0 0
1 0 0 0 0 0 0 0 0
2 2 2 2 2 1 1 1 0
2 0 0 0 1 3 3 0 0
0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 1 1 0
0 0 0 0 0 0 1 1 0
0 0 0 0 0 0 0 0 0
0 0 0 1 1 0 2 0 0
0 0 1 1 0 1 1 1 0
1 2 2 1 1 1 1 0 0
0 2 2 1 1 1 1 0 0
0 0 1 1 1 1 1 0 0
0 1 1 1 1 1 1 0 0
0 0 0 0 1 0 0 1 1
0 0 0 0 0 1 1 0 2
0 0 0 0 0 0 0 0 0
0 1 0 0 1 0 0 0 0
1 1 1 1 1 1 2 3 2
0 none, 1 slight, 2 moderate, 3 severe, 4 very severe.
Vol. 24 No. 6 December 2002
Nasal Morphine-Chitosan for Breakthrough Pain
Fig. 1. Mean pain intensity and relief after nasal morphine-chitosan (n 20).
characteristics aid drug absorption. The venous blood drains from the nose directly into the systemic circulation, avoiding hepatic first-pass metabolism. Drugs with a small molecular weight that are predominantly lipophilic are most rapidly absorbed.15 Hydrophilic drugs can be removed from the nasal cavity by the mucociliary clearance mechanism before sufficient absorption can occur. Chitosan is a linear cationic polysaccharide, produced from chitin extracted from crustacean shells, and acts as a bio-adhesive material by binding strongly to negatively charged biological surfaces such as mucus membranes. The clearance from the nasal cavity of formulations containing chitosan is thus delayed, increasing the time available for drug absorption.6 The addition of chitosan to morphine increases its nasal bio-availability from about 10% to 54%, with a time to maximum concentration of 15 minutes.7 Chitosan is not absorbed, is bio-compatible, non-toxic, and lacks irritant or allergic effects.16 The administration of nasal morphine-chitosan appears acceptable to patients, with the majority rating their overall satisfaction as good or very good. The formulation was well tolerated nasally, with reported symptoms generally mild and transient except for a ‘severe’ bitter taste, most likely the result of clearance of some morphine into the oropharynx. The doses that were studied would provide the dose of breakthrough analgesia required by most patients. The most frequent non-nasal adverse effect was sedation, reported in 16 episodes (Table 2). In 8 episodes, sedation appeared temporally related to the administration of nasal morphine-chitosan. It is difficult to explore this
601
fully, in an uncontrolled study, however, particularly in the presence of other factors that may contribute to sedation. A controlled and blinded comparison with oral morphine would be useful in this regard. The incidence of sedation could suggest that the use of a nasal to oral dose ratio of 1:1 is excessive. The mean (range) oral bio-availability of morphine is reported as 38% (15–64%).2 In the elderly, due to reduced hepatic metabolism, bio-availability is likely to be at the upper end of the range, approximating that seen after nasal administration, and formed the rationale for the 1:1 ratio.7,17 Dose-titration or relative potency studies of oral and nasal morphine are needed to explore this further. Nasal morphine-chitosan appears to have a rapid onset of effect. Reports of pain relief and of reduced pain intensity were seen after only 5 minutes, progressively improving until reaching a maximum after 45 minutes. Confirmation is required in controlled studies that include oral morphine and oral transmucosal fentanyl citrate as comparators. In conclusion, this pilot study suggests that nasal morphine-chitosan formulation is acceptable to patients, is generally well tolerated, and may lead to rapid onset of pain relief. This formulation has the potential to allow morphine, a commonly used opioid for the relief of cancer pain, to be given in a way that is more rapidly effective and more convenient than the oral route. This could be of particular benefit to patients at home, and for those unable to swallow or who are vomiting. We believe this formulation warrants further examination in controlled studies.
Acknowledgment The authors would like to thank West Pharmaceutical Services for the manufacture, release, and supply of the nasal morphine-chitosan formulation and for contributing towards the costs of this study.
References 1. Hanks GWC, De Conno F, Cherny N, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Brit J Cancer 2001;84:587– 593.
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Pavis et al.
2. Twycross RG, Wilcock A, Charlesworth S, Dickman A. Palliative Care Formulary (2nd Ed.). Oxon: Radcliffe Medical Press, 2002. 3. Collins SL, Faura CC, Moore A, McQuay HJ. Peak plasma concentrations after oral morphine: a systematic review. J Pain Symptom Manage 1998;16:388–402. 4. Wilcock A. New approaches to pain management. Prog in Pall Care 2001;9:100–101. 5. Soane RJ, Frier M, Perkins AC, et al. Evaluation of the clearance characteristics of bio-adhesive systems in humans. Int J Pharm 1999;178:55–65. 6. Illum L, Farraj NF, Davis SS. Chitosan as a novel nasal delivery system for peptide drugs. Pharm Res 1994;11:1186–1189. 7. West Pharmaceutical Services, data on file. 8. Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: characteristics and impact in patients with cancer pain. Pain 1999;81:129–134. 9. Swanwick M, Haworth M, Lennard RF. The prevalence of episodic pain in cancer: survey of hospice patients on admission. Palliat Med 2001;15:9–18. 10. Farrar JT, Cleary J, Rauck R, et al. Oral transmucosal fentanyl citrate: randomized double- blinded, placebo-controlled trial for treatment of breakthrough pain in cancer patients. J Natl Cancer Inst 1998;90: 611–616.
Vol. 24 No. 6 December 2002
11. Christie JM, Simmonds M, Patt R et al. Dosetitration, multicenter study of oral transmucosal fentanyl citrate for the treatment of breakthrough pain in cancer patients using transdermal fentanyl for persistent pain. J Clin Oncol 1998;16:3238–3245. 12. Wilson JA, Kendall JM, Cornelius P. Intranasal diamorphine for paediatric analgesia: assessment of safety and efficacy. J Accid Emerg Med 1997;14: 70–72. 13. Striebel HW, Wessel A, Rieger A, Boerger N. Intranasal fentanyl for breakthrough cancer pain or incident pain. Br J Anaesth 1993;70:A210,109. 14. Zeppetella G. Nebulized and intranasal fentanyl in the management of cancer-related breakthrough pain. Palliat Med 2000;14:57–58. 15. Illum L, Fisher AN. Intranasal delivery of peptides and proteins. In: Adjei AL, Gupta PK, eds. Inhalation delivery of therapeutic peptides and proteins. New York: Marcel Dekker Inc, 1997:135– 184. 16. Dodane V, Vilivalam V. Pharmaceutical applications of chitosan. Pharm Sci Tech Today 1998;1: 246–253. 17. Baillie SP, Bateman DN, Coates PE, Woodhouse KW. Age and the pharmacokinetics of morphine. Age Ageing 1989;18:258–262.
Journal of Pain and Symptom Management
Vol. 24 No. 6 December 2002
Clinical Note
Pilot Study of Nasal Morphine-Chitosan for the Relief of Breakthrough Pain in Patients With Cancer Hilary Pavis, MA, MRCGP, Andrew Wilcock, DM, FRCP, Jane Edgecombe, MRCP, Diane Carr, RGN, Cathann Manderson, RGN, Ann Church, PhD, and Anthony Fisher, PhD Hayward House Macmillan Specialist Palliative Care Unit (H.P., A.W., J.E., D.C., C.M.), Nottingham City Hospital NHS Trust, and West Pharmaceutical Services (A.C., A.F.), Albert Einstein Center, Nottingham Science and Technology Park, Nottingham, United Kingdom
Abstract Breakthrough pain in patients with cancer is common, often unpredictable, and can rapidly become severe. Treatment using the oral administration of opioids is not optimal due to the slow onset of pain relief. Nasal administration of analgesics potentially offers more rapid pain relief. This study investigates the tolerability and efficacy of a novel morphine-chitosan formulation. Twenty episodes of breakthrough pain were observed in 14 patients with cancer who received 5–80 mg of nasal morphine-chitosan. Nasal symptoms, sedation, giddiness, nausea, and other volunteered symptoms, along with pain scores (pain intensity and pain relief), were recorded at baseline and at regular intervals up to 4 hours after administration, together with an overall satisfaction rating. The formulation was acceptable to patients, generally well tolerated, and had an onset of pain relief 5 minutes after dosing. This formulation warrants further study. J Pain Symptom Manage 2002;24:598–602. © U.S. Cancer Pain Relief Committee, 2002. Key Words Cancer, pain, breakthrough pain, morphine, nasal drugs
Introduction Morphine, given regularly by mouth, is commonly recommended for the relief of cancer pain.1 Breakthrough pain, a transitory exacerbation of pain in a patient who has mainly stable and adequately controlled pain, is generally treated with an additional dose of immediate-
Address reprint requests to: Andrew Wilcock, DM, FRCP, Hayward House Macmillan Specialist Palliative Care Unit, Nottingham City Hospital NHS Trust, Hucknall Road, Nottingham NG5 1PB, United Kingdom. Accepted for publication: January 19, 2002. © U.S. Cancer Pain Relief Committee, 2002 Published by Elsevier, New York, New York
release morphine, administered orally as a solution or tablet. Onset of pain relief may take 20– 30 minutes and peak analgesia one hour or more, in keeping with a mean (range) time to maximum plasma concentration of 1.1 (0.2– 3.5) hours.2,3 Parenteral administration provides a more rapid onset of pain relief, but is not always an available, convenient, or preferred option. Thus, other non-oral routes of administration, such as transmucosal, nasal, or pulmonary, that may provide convenient and rapid pain relief are worth pursuing.4 The nasal route of administration is potentially the most convenient alternative method for drug delivery. Nasal drug absorption is 0885-3924/02/$–see front matter PII S0885-3924(02)00522-5
Vol. 24 No. 6 December 2002
Nasal Morphine-Chitosan for Breakthrough Pain
aided by a highly vascular epithelium, a large surface area and the avoidance of first pass metabolism. Morphine however, being hydrophilic, is poorly absorbed nasally. This problem may be overcome by combining morphine with chitosan, a bio-adhesive material that slows the mucociliary clearance of morphine, allowing more time for absorption.5,6 In healthy volunteers, nasal morphine-chitosan is well tolerated, and has mean values for bioavailability, time to peak plasma concentration and elimination half-life of 56%, 15 minutes, and 3 hours, respectively.7 In this pilot study, we have examined, for the first time, the tolerability and efficacy of a nasal morphine-chitosan solution in patients.
Methods Subjects were inpatients at a specialist palliative care unit. All had cancer-related pain treated with regularly scheduled opioid administration and all experienced episodes of breakthrough pain, for which they used and found effective, additional doses of oral morphine. Episodes of breakthrough pain treated with nasal morphine-chitosan were of at least of moderate severity (i.e., 2 on the pain scale) and occurred more than one hour after any immediate-release morphine preparation. All regularly prescribed analgesics were continued. A maximum of two episodes was observed per patient. Patients were excluded if too frail or unwell to participate, psychological distress significantly contributed to their pain, or if their nasal passages were abnormal, congested, or occluded. Nasal morphine was administered by research staff in a standardized way using the same dose that the patient received orally for episodes of breakthrough pain. Two preparations of morphine-chitosan were supplied, 5 mg/0.1 ml and 20 mg/0.1 ml; this allowed morphine doses in the range of 5–80mg to be administered in 1–4 sprays from Pfeiffer single 0.1ml unit dosing devices (maximum of two sprays per nostril). Nasal symptoms (sore, itching or stinging nose, sore or stinging throat, dry or stuffy nose, runny nose, or taste disturbance), sedation, giddiness, nausea and other volunteered symptoms, along with pain scores (pain intensity and pain relief), were recorded at baseline and
599
at regular intervals up to 4 hours after administration. Nasal symptoms, sedation, giddiness, nausea, and other symptoms were assessed on a scale of 0–4, where 0 represents ‘none’ and 4 ‘very severe’. Pain intensity was recorded on a scale of 0–4, where 0 represents ‘no pain’ and 4 ‘very severe’ pain. Pain relief was assessed on a scale of 4 to 4, where 4 represents ‘complete relief’ and 4 ‘pain has become maximal’. At the end of the study, patients were asked to provide an overall satisfaction rating of excellent, very good, good, fair, or poor. All patients gave written informed consent and the study was approved by Nottingham City Hospital Research Ethics Committee.
Results Twenty episodes of pain were observed in 14 patients. There were 9 men and 5 women. The mean (range) age and World Health Organization performance status were 66 (44–79) years and 2.4 (1–3), respectively. In accordance with their usual dose of oral morphine for breakthrough pain, patients received one or two doses of 5 mg (3 patients), 10 mg (3 patients), 15 mg (2 patients), 20 mg (4 patients), 30 mg (1 patient) or 80 mg (1 patient) of nasal morphine.
Overall Satisfaction Patients rated the 20 episodes with nasal morphine-chitosan as ‘excellent’ (1), ‘very good’ (6), ‘good’ (11) and ‘fair’ (2).
Tolerability The majority of nasal symptoms were rated as 0 ‘none’ or 1 ‘slight,’ and were transient in nature (Table 1). ‘Severe’ taste disturbance was reported in 4 episodes and appeared dose related. This occurred 5 minutes after dose administration in 3 patients, who described it as a bitter taste; in the fourth patient, it was reported prior to drug administration and remained unchanged throughout the study. The most frequent non-nasal adverse effect was sedation, reported at some point during 16 episodes. In 8 episodes, it appeared temporally related to the nasal morphine and, at its worst, patients rated it as ‘very severe’ (1), ‘moderate’ (2) or ‘mild’ (5). During two episodes, sedation that was reported at baseline subsequently worsened following treatment. Baseline seda-
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Pavis et al.
Vol. 24 No. 6 December 2002
Table 1 Incidence (%) of Each Assessment Score and the Number of Episodes of Breakthrough Pain Recording that Score No. of Episodes with a Score of:
Incidence (%) of Score Variable Sore/stinging nose Dry/stuffy nose Runny nose Sore/stinging throat Taste disturbance Nausea Sedation Giddiness Other symptomsa
0 none
1 slight
2 moderate
3 severe
4 very severe
0
1
2
3
4
149 (83) 150 (83) 158 (88) 149 (83) 121 (67) 158 (88) 101 (56) 158 (88) 4 (16)
24 (13) 21 (12) 19 (11) 24 (13) 36 (20) 18 (10) 47 (26) 18 (10) 11 (44)
6 (3) 9 (5) 3 (2) 6 (3) 12 (7) 4 (2) 26 (14) 2 (1) 6 (24)
1 (1) 0 (0) 0 (0) 1 (1) 11 (6) 0 (0) 5 (3) 2 (1) 1 (4)
0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 3 (12)
20 20 20 20 20 20 20 20 3
11 6 6 9 13 7 16 7 4
5 1 2 5 7 2 9 1 4
1 0 0 1 4 0 4 1 1
0 0 0 0 0 0 1 0 1
The total number of assessments for each variable was 180 (20 episodes 9 assessments). aOther symptoms (dry mouth/throat, light headedness, muscle aches) were recorded in 5 episodes (25 assessment scores in total).
tion improved or stayed unchanged following treatment in two episodes each (Table 2). One patient reported a ‘very severe’ dry mouth. This was present prior to administration, persisted over the first 15 minutes after dosing, and subsequently improved to ‘slight’ over the duration of the study.
Discussion Breakthrough pain in patients with cancer is common, often unpredictable and can be severe.8,9 Morphine given orally, although commonly used, is not optimal due to the slow onset of pain relief. Parenteral administration provides a more rapid onset of pain relief, but is not always available or convenient. Exploration of other routes of analgesic administration for the treatment of breakthrough pain has seen the development of the oral transmucosal fentanyl citrate lozenge, which provides more rapid onset pain relief than oral morphine.10,11 This formulation has some limitations; the effective dose for a patient is difficult to predict and requires dose titration, it is unsuitable in approximately 25% of patients, and is expensive. We, like others, have explored the delivery of strong opioids nasally.12–14 The nose has a large surface area due to microvilli on the epithelial surface and is highly vascularized. These
Efficacy Improvements in pain intensity and relief were reported at 5 minutes and reached a maximum after 45 minutes, at which time pain intensity was rated as ‘slight’ and pain relief as ‘eased moderately’. In 9 episodes, patients received a dose of a regularly prescribed analgesic 1–4 hours after nasal morphine-chitosan. Mean pain intensity and relief scores for the first hour following administration of nasal morphine are therefore presented, as no additional regular analgesic was administered during this period (Figure 1).
Table 2 Assessment Scores of Sedation Following Nasal Morphine-Chitosan Episode number Time (min)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
0 5 15 30 45 60 120 180 240
2 3 4 2 1 2 2 2 2
0 0 0 0 0 0 0 0 0
1 0 0 0 0 0 0 0 0
2 2 2 2 2 1 1 1 0
2 0 0 0 1 3 3 0 0
0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 1 1 0
0 0 0 0 0 0 1 1 0
0 0 0 0 0 0 0 0 0
0 0 0 1 1 0 2 0 0
0 0 1 1 0 1 1 1 0
1 2 2 1 1 1 1 0 0
0 2 2 1 1 1 1 0 0
0 0 1 1 1 1 1 0 0
0 1 1 1 1 1 1 0 0
0 0 0 0 1 0 0 1 1
0 0 0 0 0 1 1 0 2
0 0 0 0 0 0 0 0 0
0 1 0 0 1 0 0 0 0
1 1 1 1 1 1 2 3 2
0 none, 1 slight, 2 moderate, 3 severe, 4 very severe.
Vol. 24 No. 6 December 2002
Nasal Morphine-Chitosan for Breakthrough Pain
Fig. 1. Mean pain intensity and relief after nasal morphine-chitosan (n 20).
characteristics aid drug absorption. The venous blood drains from the nose directly into the systemic circulation, avoiding hepatic first-pass metabolism. Drugs with a small molecular weight that are predominantly lipophilic are most rapidly absorbed.15 Hydrophilic drugs can be removed from the nasal cavity by the mucociliary clearance mechanism before sufficient absorption can occur. Chitosan is a linear cationic polysaccharide, produced from chitin extracted from crustacean shells, and acts as a bio-adhesive material by binding strongly to negatively charged biological surfaces such as mucus membranes. The clearance from the nasal cavity of formulations containing chitosan is thus delayed, increasing the time available for drug absorption.6 The addition of chitosan to morphine increases its nasal bio-availability from about 10% to 54%, with a time to maximum concentration of 15 minutes.7 Chitosan is not absorbed, is bio-compatible, non-toxic, and lacks irritant or allergic effects.16 The administration of nasal morphine-chitosan appears acceptable to patients, with the majority rating their overall satisfaction as good or very good. The formulation was well tolerated nasally, with reported symptoms generally mild and transient except for a ‘severe’ bitter taste, most likely the result of clearance of some morphine into the oropharynx. The doses that were studied would provide the dose of breakthrough analgesia required by most patients. The most frequent non-nasal adverse effect was sedation, reported in 16 episodes (Table 2). In 8 episodes, sedation appeared temporally related to the administration of nasal morphine-chitosan. It is difficult to explore this
601
fully, in an uncontrolled study, however, particularly in the presence of other factors that may contribute to sedation. A controlled and blinded comparison with oral morphine would be useful in this regard. The incidence of sedation could suggest that the use of a nasal to oral dose ratio of 1:1 is excessive. The mean (range) oral bio-availability of morphine is reported as 38% (15–64%).2 In the elderly, due to reduced hepatic metabolism, bio-availability is likely to be at the upper end of the range, approximating that seen after nasal administration, and formed the rationale for the 1:1 ratio.7,17 Dose-titration or relative potency studies of oral and nasal morphine are needed to explore this further. Nasal morphine-chitosan appears to have a rapid onset of effect. Reports of pain relief and of reduced pain intensity were seen after only 5 minutes, progressively improving until reaching a maximum after 45 minutes. Confirmation is required in controlled studies that include oral morphine and oral transmucosal fentanyl citrate as comparators. In conclusion, this pilot study suggests that nasal morphine-chitosan formulation is acceptable to patients, is generally well tolerated, and may lead to rapid onset of pain relief. This formulation has the potential to allow morphine, a commonly used opioid for the relief of cancer pain, to be given in a way that is more rapidly effective and more convenient than the oral route. This could be of particular benefit to patients at home, and for those unable to swallow or who are vomiting. We believe this formulation warrants further examination in controlled studies.
Acknowledgment The authors would like to thank West Pharmaceutical Services for the manufacture, release, and supply of the nasal morphine-chitosan formulation and for contributing towards the costs of this study.
References 1. Hanks GWC, De Conno F, Cherny N, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Brit J Cancer 2001;84:587– 593.
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Pavis et al.
2. Twycross RG, Wilcock A, Charlesworth S, Dickman A. Palliative Care Formulary (2nd Ed.). Oxon: Radcliffe Medical Press, 2002. 3. Collins SL, Faura CC, Moore A, McQuay HJ. Peak plasma concentrations after oral morphine: a systematic review. J Pain Symptom Manage 1998;16:388–402. 4. Wilcock A. New approaches to pain management. Prog in Pall Care 2001;9:100–101. 5. Soane RJ, Frier M, Perkins AC, et al. Evaluation of the clearance characteristics of bio-adhesive systems in humans. Int J Pharm 1999;178:55–65. 6. Illum L, Farraj NF, Davis SS. Chitosan as a novel nasal delivery system for peptide drugs. Pharm Res 1994;11:1186–1189. 7. West Pharmaceutical Services, data on file. 8. Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: characteristics and impact in patients with cancer pain. Pain 1999;81:129–134. 9. Swanwick M, Haworth M, Lennard RF. The prevalence of episodic pain in cancer: survey of hospice patients on admission. Palliat Med 2001;15:9–18. 10. Farrar JT, Cleary J, Rauck R, et al. Oral transmucosal fentanyl citrate: randomized double- blinded, placebo-controlled trial for treatment of breakthrough pain in cancer patients. J Natl Cancer Inst 1998;90: 611–616.
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