TITLE: for Palliative Pain Relief: A Review of the Clinical Effectiveness, Cost- Effectiveness and Guidelines

DATE: 18 November 2015

CONTEXT AND POLICY ISSUES

Palliative care is defined by the World Health Organization (WHO) as ―an approach that improves the quality of life of patients and their families facing the problems associated with life- threatening illness, through the prevention and relief of suffering by means of identification and impeccable assessment and treatment of pain and other physical, psychosocial and spiritual problems‖.1 Pain is a frequent component in the constellation of health burdens that occur during end of life treatment and is an important target of palliative care. The Canadian National Palliative Care survey of cancer patients referred for palliative care or admitted to palliative care units across Canada reported that 70% of patients had daily pain, which was considered moderate or worse in 48% of cases.2 The presence of pain during end of life care is common in patients with cancer, HIV infection and AIDS, multiple sclerosis, cardiovascular disease, and dementia.3 In addition to substantial detriment to quality of life, pain may hinder an individual‘s ability to complete important tasks like putting affairs in order at end of life.4

The WHO has stated that all patients have a right to receive treatment for their pain at end of life.5 Palliative care patients differ from non-palliative patients in that the focus of treatment shifts to symptom management and maintenance of quality of life. Therefore, some of the concerns surrounding pain medication such as risk of addiction may be reduced. Accordingly, criteria for provision of medications differ. For instance, the Ontario Drug Benefit enables exceptional access to certain treatments including for palliative care patients.6 In 2013, the WHO recommended and in various formulations as essential medicines in palliative care due to demonstrated efficacy of morphine for severe pain and insufficient evidence to support one NSAID over another.1 Cancer Care Ontario suggests the provision of opioids (morphine, , or ) for cancer patients with moderate to severe pain.7 Opioids are one of the most frequently used drug classes in palliative pain management though there is uncertainty regarding the optimal drug and dose.8

Sufentanil is a highly lipophilic analogue typically used for surgical analgesia with a proposed therapeutic role in cancer pain and opioid tolerance.9 It is a rapid-onset opioid, a

Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic review s. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts w ithin the time allow ed. Rapid responses should be considered along w ith other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are als o cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for w hich little information can be found, but w hich may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that ef fect. CADTH is not liable for any loss or damages resulting from use of the information in the report.

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group of drugs designed for breakthrough pain that can be absorbed via trans-mucosal route.10 It has approximately 10 times the potency of fentanyl, and, like fentanyl, does not have active metabolites.10 Sufentanil is likely safe for use in patients with renal failure and doesn‘t decrease bowel transit time or induce nausea and vomiting to the same extent as alternative opioids.11-14 Yet, like other opioids there is a risk of skin irritation, bradycardia and other cardiovascular concerns, somnolence and CNS depression, chest wall rigidity, and blurred vision.9

Sufentanil is currently indicated for surgical procedures as an intravenous or epidural anesthetic agent so use in pain management outside of this context is off-label. Off-label use of sublingual sufentanil for breakthrough cancer pain has been noted in Canada.10,15 There is evidence for the efficacy of sufentanil in pain management, but evidence specific to the context of palliative care is limited. Sufentanil has been observed in small non-randomized studies and case studies to improve breakthrough pain in patients (primarily with cancer) receiving palliative care.16-20

Despite the off-label indication and lack of evidence, sufentanil for palliative pain relief has been mentioned in the Canadian context. Both the British Columbia Ministry of Health21 and Fraser Health22 — a provincial health authority in Metro Vancouver — mention sufentanil within clinical practice guidelines for palliative care. These guidelines do not recommend giving sufentanil to opioid naïve patients unless by a palliative care specialist,21 provide guidance for dosing,21 and caution against using sufentanil for incident pain when other immediate release or long acting opioids are being used.22

Sufentanil is considerably more expensive than short-acting opioids like oral morphine and hydromorphone.10,22 The cost of palliative care per patient in Canada was estimated to be approximately $26,000 CAD in urban areas and $31,000 in rural areas, with families assuming approximately 20% of the cost.23 This highlights the importance of identifying the most cost- effective approaches to elements of palliative care such as pain management.

An evaluation of the evidence behind the use of sufentanil in palliative pain relief is warranted given the proposed and observed off-label use in palliative care, and the mention of sufentanil within palliative care guidelines. Further, the relatively high cost of sufentanil necessitates an evaluation of resource implications. This report will review the evidence on clinical effectiveness and cost-effectiveness, as well as evidence-based guidelines regarding sufentanil for pain relief specifically in the context of palliative care.

RESEARCH QUESTIONS

1. What is the clinical effectiveness of sufentanil for relief of palliative pain?

2. What is the cost-effectiveness of sufentanil for relief of palliative pain?

3. What are the evidence-based guidelines regarding the palliative use of sufentanil?

KEY FINDINGS

One systematic review was identified regarding the clinical effectiveness of sufentanil for the relief of palliative pain. It identified one poor quality study suggesting that there is insufficient evidence to draw conclusions regarding the clinical effectiveness of sufentanil use in the context of palliative care. In addition, no cost-effectiveness analyses or current evidence-based guidelines were identified on this topic.

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METHODS

Literature Search Methods

A limited literature search was conducted on key resources including PubMed, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2010 and October 22, 2015.

Rapid Response reports are organized so that the evidence for each research question is presented separately.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Table 1: Selection Criteria Population Patients receiving palliative care Intervention Sufentanil Comparator Drugs used for palliative pain (e.g., morphine, fentanyl, oxycodone dimepheptanol, , ); No comparator Outcomes Q1: Clinical effectiveness (e.g., pain relief); Harms (e.g., kidney damage, constipation) Q2: Cost-effectiveness Q3: Guidelines Study Designs Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, non-randomized studies, economic evaluations, evidence-based guidelines

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, or were published prior to 2010. Health technology assessment reports, systematic reviews (SR), meta-analyses, and evidence-based guidelines were excluded if there was incomplete reporting of methodology or if they were superseded by a more recent, rigorous, or updated review or guideline. Randomized controlled trials and non-randomized studies were excluded if they were included within a selected SR.

Critical Appraisal of Individual Studies

The included SRs were critically appraised using AMSTAR criteria.24 The methods used when conducting the literature search, study selection, data extraction, quality assessment, and for

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summarizing the data were assessed. Summary scores were not calculated; rather, the strengths and limitations of each included study are described narratively.

SUMMARY OF EVIDENCE

Quantity of Research Available

A total of 390 citations were identified in the literature search. Following screening of titles and abstracts, 388 citations were excluded and two potentially relevant reports from the electronic search were retrieved for full-text review. One potentially relevant publication was retrieved from the grey literature search. Of these three potentially relevant articles, one publication was excluded because of publication type (non-systematic review article), and one evidence-based guideline was excluded as it did not mention sufentanil.25 One publication26 met the inclusion criteria and was included in this report. Appendix 1 describes the PRISMA flowchart of the study selection.

Summary of Study Characteristics

Detailed study characteristics are summarized in Appendix 2.

Study Design

One SR26 was identified regarding the clinical effectiveness of sufentanil for the relief of palliative. It searched evidence from database inception to July 2009 and identified prospective and retrospective non-randomized studies. Of the 15 studies included, one retrospective study (published as a letter to the editor in 2008) investigated the clinical effectiveness of sufentanil.12 The other studies assessed other opioids. Results were described narratively and no meta- analysis of studies was conducted.

Country of Origin

The SR26 and the single sufentanil-related study12 included in the review were both conducted by authors located in the UK.

Patient Population

Studies on patients with cancer-related pain and renal impairment were included in the systematic review.26 While palliative status was not explicitly stated, the study was published in a palliative care journal and the single study12 referring to sufentanil as the intervention specified inclusion of palliative care patients.

Interventions and Comparators

The clinical effectiveness of a range of opioids, including sufentanil was assessed.26 The single relevant sufentanil study did not include any comparators. Sufentanil was administered as a continuous subcutaneous infusion starting with a median dose of 95 mcg per hour (range = 15 to 600 mcg per hour) which was adjusted to a median dose of 130 mcg/hour (range = 15 to 700 mcg per hour).

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Outcomes

While many different outcomes related to pain, function, safety and quality of life were considered by the studies included in the SR,26 the one included sufentanil study12 did not consider formal outcome measures and only discussed the quality of pain control descriptively. No formal methods of measuring pain were reported.

Summary of Critical Appraisal

A summary of study strengths and limitations is presented in Appendix 3.

The SR26 was well conducted. A non-published a priori protocol was referenced. Duplicate study selection and extraction was not explicitly stated, but reference was made to three authors being involved in the process. A comprehensive literature search was conducted on multiple databases as well as a comprehensive grey literature search. A list of included studies and study characteristics was provided, but a list of excluded studies was not. All studies were assessed for quality using GRADE criteria. Results were presented narratively as there was insufficient evidence to perform a meta-analysis. A high likelihood of publication bias was stated, but the method of assessment was unclear. Both funding sources and conflict of interest (none) were disclosed. The single study assessing sufentanil was difficult to interpret as it was published within a letter to the editor and had several reporting deficiencies. Further, this study did not report any clear efficacy outcomes or adverse events.

Summary of Findings

Detailed study findings are presented in Appendix 4.

What is the clinical effectiveness of sufentanil for relief of palliative pain?

This single study concerning sufentanil12 within the SR26 reported that provision of a continuous subcutaneous infusion of sufentanil to cancer patients receiving palliative care and who had previously received other opioids resulted in ―generally favorable‖ responses for pain control.

What is the cost-effectiveness of sufentanil for relief of palliative pain?

No evidence was identified regarding the cost-effectiveness of sufentanil for relief of palliative pain; therefore, no summary can be provided.

What are the evidence-based guidelines regarding the palliative use of sufentanil?

No evidence-based guidelines were identified regarding the palliative use of sufentanil; therefore, no summary can be provided.

Limitations

Reporting

The sufentanil study12 within the SR26 was published within a letter to the editor, and consequently, reporting was abbreviated and incomplete. There was very limited information provided regarding study design, patient characteristics, and outcome measures.

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Outcome Measures

The outcome measure of ‗effect on pain control‘ was reported descriptively. It is unclear how this outcome was measured; therefore, the reliability and validity of this outcome and the findings, in general, could not be verified.

Generalizability

The evidence presented for this study only pertains to sufentanil used as a continuous subcutaneous infusion, not the transdermal sublingual route most commonly proposed for palliative care patients. As such, the generalizability of these findings for other routes of administration may be limited. Similarly, this study concerned cancer patients so it is unclear how this evidence might apply to non-cancer patients receiving palliative care. Patients were not opioid naïve so the study does not describe the appropriateness of sufentanil for patients who had not previously been treated with opioids.

CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING

There is insufficient evidence to draw conclusions on the clinical effectiveness or cost- effectiveness of sufentanil in the context of palliative pain relief. Further, there are no recent evidence-based guidelines providing recommendations regarding the use of sufentanil in palliative care.

The included SR26 was conducted to support a guideline development process aimed at making recommendations for the use of opioid in the treatment of cancer pain. The published guideline could not include any recommendations specific to sufentanil due to insufficient evidence.25 The single study12 identified regarding the use of sufentanil in a palliative care setting suggested a benefit to patients in terms of pain control, but reporting deficiencies and the lack of formal outcome measures suggest that these results are unreliable.

Current use of sufentanil to control breakthrough pain is off-label and informed by clinical expertise and patterns of practice rather than direct evidence. Further research on the use of sufentanil in palliative care patients is required to inform appropriate use in this context. Some relevant issues to consider include the ability of palliative care patients with cognitive conditions (e.g., dementia) to hold sublingual preparations in their mouth for the instructed 1 to 2 minutes,19 uncertainty regarding appropriate doses, lack of consensus on dose equivalency of sufentanil versus other opioids,27 potential adverse effects such as exacerbation or onset of respiratory depression, and risks of concurrent use of other opioids or CYP3A4 inhibitors.19 With the recent development of a sufentanil sublingual tablet system (Zalviso; currently not approved by the FDA or Health Canada) as an alternative to intravenous patient-controlled analgesia, the comparative efficacy of different routes of administration also warrants investigation.

PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca

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REFERENCES

1. International Association for Hospice and Palliative Care (IAHPC). Essential medicines in palliative care: executive summary [Internet]. Houston (TX): World Health Organization; 2013 [cited 2015 Nov 10]. Available from: http://www.who.int/selection_medicines/committees/expert/19/applications/PalliativeCare_ 8_A_R.pdf

2. Wilson KG, Chochinov HM, Allard P, Chary S, Gagnon PR, Macmillan K, et al. Prevalence and correlates of pain in the Canadian National Palliative Care Survey. Pain Res Manag. 2009 Sep;14(5):365-70. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779154

3. Broglio K, Portenoy RK. Pain assessment and management in the last weeks of life. 2015 Oct 23 [cited 2015 Nov 6]. In: UpToDate [Internet]. Waltham (MA): UpToDate; c2005 - . Available from: www.uptodate.com Subscription required.

4. Jackson V, Nabati L. Ethical considerations in effective pain management at the end of life. 2015 Oct 14 [cited 2015 Nov 6]. In: [Internet]. Waltham (MA): UpToDate; c2005 - . Available from: www.uptodate.com Subscription required.

5. Cancer pain relief and palliative care. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser. 1990 [cited 2015 Nov 11];804:1-75.

6. Ontario drug benefit formulary/comparative drug index [Internet]. 42. Toronto (ON): Ministry of Health and Long-Term Care; 2015 Sep 30 [cited 2015 Nov 11]. Available from: http://www.health.gov.on.ca/en/pro/programs/drugs/formulary42/edition_42.pdf

7. Cancer Care Ontario. Cancer Care Ontario's symptom management pocket guides: pain [Internet]. Toronto (ON): Cancer Care Ontario; 2010 [cited 2015 Nov 11]. Available from: https://www.cancercare.on.ca/CCO_DrugFormulary/Pages/FileContent.aspx?fileId=97479

8. Droney J, Levy J, Quigley C. Prescribing opioids in renal failure. J Opioid Manag. 2007 Nov;3(6):309-16.

9. Sufentanil: drug information. 2015 [cited 2015 Nov 11]. In: UpToDate [Internet]. Waltham (MA): UpToDate; c2005 - . Available from: www.uptodate.com Subscription required.

10. Doulton B. Pharmacologic management of adult breakthrough cancer pain. Can Fam Physician [Internet]. 2014 Dec [cited 2015 Nov 11];60(12):1111-9. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264807

11. Niscola P, Scaramucci L, Vischini G, Giovannini M, Ferrannini M, Massa P, et al. The Use of major analgesics in patients with renal dysfunction. Curr Drug Targets. 2010 Jun;11(6):752-8.

12. White C, Hardy J, Boyd A, Hall A. Subcutaneous sufentanil for palliative care patients in a hospital setting. Palliat Med. 2008 Jan;22(1):89-90.

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13. Ahmedzai S, Brooks D. Transdermal fentanyl versus sustained-release oral morphine in cancer pain: preference, efficacy, and quality of life. The TTS-Fentanyl Comparative Trial Group. J Pain Symptom Manage. 1997 May;13(5):254-61.

14. Maciejewski D. Sufentanil in anaesthesiology and intensive therapy. Anaesthesiol Intensive Ther. 2012 Jan;44(1):35-41.

15. Cancer Care Ontario's symptom management guides-to-practice: pain [Internet]. Toronto (ON): Cancer Care Ontario; 2010 [cited 2015 Nov 11]. Available from: https://www.cancercare.on.ca/CCO_DrugFormulary/Pages/FileContent.aspx?fileId=97481

16. Paix A, Coleman A, Lees J, Grigson J, Brooksbank M, Thorne D, et al. Subcutaneous fentanyl and sufentanil infusion substitution for morphine intolerance in cancer pain management. Pain. 1995 Nov;63(2):263-9.

17. Kunz KM, Theisen JA, Schroeder ME. Severe episodic pain: management with sublingual sufentanil. J Pain Symptom Manage. 1993 May;8(4):189-90.

18. Jackson K, Keech J. Pilot dose finding study of intranasal sufentanil for breakthrough and incident pain cancer-associated pain [letter]. J Pain Symptom Manage [Internet]. 2002 [cited 2015 Nov 11];23(6). Available from: http://intranasal.net/Peer%20Reviewed%20literature/Jackson,%20IN%20sufentanil%20in %20breakthrough%20pain,%20J%20Pain%20and%20Symp%20Management%202002.p df

19. Passmore MJ. Sublingual sufentanil for incident pain and dementia-related response agitation. Int Psychogeriatr. 2011 Jun;23(5):844-6.

20. Hilliard N, Brown S, Mitchinson S. A case report of dexmedetomidine used to treat intractable pain and delirium in a tertiary palliative care unit. Palliat Med. 2015 Mar;29(3):278-81.

21. Guidelines & Protocols Advisory Committee. Palliative care for the patient with incurable cancer or advanced disease part 2: pain and symptom management pain management [Internet]. Victoria: British Columbia Ministry of Health; 2011 Sep 30 [cited 2015 Nov 11]. Available from: http://www2.gov.bc.ca/assets/gov/health/practitioner-pro/bc- guidelines/palliative2_pain.pdf

22. Hospice Palliative Care Program. Principles of opioid management: symptom guidelines [Internet]. Surrey (BC): Fraser Health; 2007 [cited 2015 Nov 11]. Available from: https://www.fraserhealth.ca/media/16FHSymptomGuidelinesOpioid.pdf

23. Dumont S, Jacobs P, Turcotte V, Turcotte S, Johnston G. Palliative care costs in Canada: a descriptive comparison of studies of urban and rural patients near end of life. Palliat Med. 2015 Jun 3.

24. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol [Internet]. 2007 [cited 2015 Nov 11];7:10. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810543/pdf/1471-2288-7-10.pdf

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25. Caraceni A, Hanks G, Kaasa S, Bennett MI, Brunelli C, Cherny N, et al. Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC. Lancet Oncol. 2012 Feb;13(2):e58-e68.

26. King S, Forbes K, Hanks GW, Ferro CJ, Chambers EJ. A systematic review of the use of opioid medication for those with moderate to severe cancer pain and renal impairment: a European Palliative Care Research Collaborative opioid guidelines project. Palliat Med. 2011 Jul;25(5):525-52.

27. Bounes V, Barthelemy R, Diez O, Charpentier S, Montastruc JL, Ducasse JL. Sufentanil is not superior to morphine for the treatment of acute traumatic pain in an emergency setting: a randomized, double-blind, out-of-hospital trial. Ann Emerg Med. 2010 Nov;56(5):509-16.

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APPENDIX 1: Selection of Included Studies

390 citations identified from electronic literature search and screened

388 citations excluded

2 potentially relevant articles retrieved for scrutiny (full text, if available)

1 potentially relevant report retrieved from other sources (grey literature, hand search)

3 potentially relevant reports

2 reports excluded: -other (review articles, editorials)(1) -Incorrect intervention (no mention of sufentanil)(1)

1 report included in review

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APPENDIX 2: Characteristics of Included Publications

Table A1: Characteristics of Included Systematic Reviews and Meta-Analyses First Author, Types and Population Intervention Comparator(s) Clinical Publication numbers of Characteristics Outcomes, Year, Country primary Length of studies Follow-Up included King, 2011,26 N = 15 studies Patients with Provision of Provision of Adverse UK cancer pain and various various opioids events, pain (n = 8 renal opioids† to to patients control, prospective, n impairment* patients with without requirement for = 8 impaired renal impaired renal opioid rotation, retrospective function function; toxicity, non- cognitive randomized Alternate route function, studies) of quality of life administration;

No comparator Sufentanil Studies Included in King et al.26 White, 2008,12 Retrospective Terminal cancer Sufentanil No comparator Described UK‡ chart review; patients with effect on pain advanced (starting dose control (no malignant 15 to 600 formal efficacy disease in the µg/24 hours, outcomes or hospital median final harms palliative care dose 130 reported) setting who µg/24 hours) were previous users of fentanyl, morphine and other opioids,

n = 48 *Noted that patient groups w ere relevant to palliative cancer care †Of the 15 included studies, one investigated sufentanil as the intervention. Other studies focused on alternative opioids including , , , , diamorphine, , pethidine (meperidine), , oxycodone, , fentanyl, alfentanil, methadone, , and ‡ Sufentanil study indicates that patients receiving palliative care w ere included UK = United Kingdom

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APPENDIX 3: Critical Appraisal of Included Publications

Table A3: Strengths and Limitations of Systematic Reviews and Meta-Analyses using AMSTAR24 Strengths Limitations King, 201126 AMSTAR Items AMSTAR Items  Reference made to ‗pre-defined, unregistered  List of excluded studies not provided protocol‘ suggesting a priori design  Insufficient evidence to conduct meta-analysis  Duplicate study selection and extraction not – only narrative summaries presented clearly stated but reference to discussion  High chance of publication bias stated but among three authors suggestive of involvement method of assessment not disclosed of at least two authors Other  Comprehensive literature search performed on  Single relevant included study published as a multiple databases as well as a thorough grey letter to the editor; therefore, there were many literature search reporting deficiencies  List of included studies and study  Study did not report formal efficacy outcomes characteristics provided or harms just generally described pain relief  All studies assessed for quality using GRADE  Quality considered in formulation of conclusions  Funding sources and conflict of interest (none) disclosed AMSTAR = Assessing the Methodological Quality of Systematic Review s; GRADE = Grading of Recommendations Assessment, Development and Evaluation

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APPENDIX 4: Main Study Findings and Author’s Conclusions

Table A5: Summary of Findings of Included Systematic Reviews Main Study Findings Author’s Conclusions King, 201126  Sufentanil produced a ‗generally favorable  Very limited low-quality evidence that sufentanil result‘ for cancer-related breakthrough pain as may be beneficial for pain relief in palliative a continuous subcutaneous infusion in patients cancer patients that was insufficient to with difficulties using other opioids formulate recommendations  Insufficient evidence or experience to make conclusions about the safety of sufentanil in this patient population – insufficient evidence to make a recommendation for chronic use

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