Alternative Routes to Oral Opioid Administration in Palliative Care: A Review and Clinical Summary

Transcription

1 Alternative Routes to Oral Opioid Administration in Palliative Care: A Review and Clinical Summary Matthew G. Kestenbaum, MD, Agustin O. Vilches, RPh, Stephanie Messersmith, MS, Stephen R. Connor, PhD, Perry G. Fine, MD, Brian Murphy, MD, Malene Davis, MBA, MSN, CHPN, J. Cameron Muir, MD

2 bs_bs_banner Pain Medicine 2014; 15: Wiley Periodicals, Inc. CANCER PAIN & PALLIATIVE CARE SECTION Review Article Alternative Routes to Oral Opioid Administration in Palliative Care: A Review and Clinical Summary Matthew G. Kestenbaum, MD,* Agustin O. Vilches, RPh, Stephanie Messersmith, MS,* Stephen R. Connor, PhD,* Perry G. Fine, MD, Brian Murphy, MD,* Malene Davis, MBA, MSN, CHPN,* and J. Cameron Muir, MD* *Capital Caring (formerly Capital Hospice), Fairfax, Virginia; Wise Hospice Options, Oklahoma City, Oklahoma; Department of Anesthesiology, Pain Management Center, School of Medicine, University of Utah, Salt Lake City, Utah, USA Reprint requests to: Matthew G. Kestenbaum, MD, Capital Caring, 2900 Telestar Court, Falls Church, VA 22042, USA. Tel: (703) ; Fax: (703) ; mkestenbaum@capitalcaring.org. Disclosures: Over the last year, Perry G. Fine, MD, has consulted for pharmaceutical companies that produce analgesics and related pain management products, including Archimedes, Ameritox, Cephalon (now Teva), Covidien, Nuvo, Nektar, Purdue Pharma, King (now Pfizer), Johnson and Johnson (Pricara/OthoMcNeil), and Mylan. Dr. Kestenbaum owns stock in Medipacs, Inc. Medipacs is a startup company that is developing a novel, nonmechanical subcutaneous pump based on polymer technology ( He has received neither consulting fees nor honoraria for his assistance. His relationship with Medipacs, Inc. had no influence on his participation in the preparation of this publication. Mr. Vilches also owns stock in Medipacs, Inc. and is a member of their professional advisory committee. His relationship with Medipacs, Inc. had no influence on his participation in the preparation of this publication. The other authors declare no conflicts of interests. Funding Source: Support to research and prepare this manuscript was provided by an unrestricted grant from Baxter Healthcare Corporation. Abstract Objective. A major goal of palliative care is to provide comfort, and pain is one of the most common causes of treatable suffering in patients with advanced disease. Opioids are indispensable for pain management in palliative care and can usually be provided by the oral route, which is safe, effective, and of lowest cost in most cases. As patients near the end of life, however, the need for alternate routes of medication increases with up to 70% of patients requiring a nonoral route for opioid administration. In order to optimize patient care, it is imperative that clinicians understand existing available options of opioid administration and their respective advantages and disadvantages. Methods. We performed a literature review to describe the most commonly used and available routes that can substitute for oral opioid therapy and to provide a summary of factors affecting choice of opioid for use in palliative care in terms of benefits, indications, cautions, and general considerations. Results. Clinical circumstances will largely dictate appropriateness of the route selected. When the oral route is unavailable, subcutaneous, intravenous, and enteral routes are preferred in the palliative care population. The evidence supporting sublingual, buccal, rectal, and transdermal gel routes is mixed. Conclusions. This review is not designed to be a critical appraisal of the quality of current evidence; rather, it is a summation of that evidence and of current clinical practices regarding alternate routes of opioid administration. In doing so, the overarching goal of this review is to support more informed clinical decision making. Key Words. Opioids; Drug Delivery Routes; Palliative Care 1129

3 Kestenbaum et al. Introduction Opioids are indispensable for pain management in palliative care, and the oral route is safe, effective, and of lowest cost in most cases. However, studies have demonstrated that as patients near the end of life, especially during the last week of life, the need for one or more alternate routes of medication increases, such that up to 70% of patients may require a nonoral route for opioid administration [1 3]. The purpose of this summary is to describe available alternatives to oral opioids in text and in table form (Table 1) with the goal of synthesizing their respective advantages, disadvantages, cautions, issues pertaining to cost, indicated populations, and/or general considerations. This review is intended to be neither an exhaustive appraisal of the literature nor a critical evaluation of the quality of evidence. Rather, it is intended to provide readers with a concise summary of the current state of the science and current practices related to alternate opioid administration (in narrative form and, for select studies of clinical importance, in table form [Tables 2 11]) so as to facilitate a better understanding of the existing literature and, in turn, hopefully lead to the provision of more evidence-based patient care. This work builds upon the excellent review from Radbruch et al. [4], who provide a systematic summary of the literature on opioid management for cancer pain as part the European Association for Palliative Care s clinical guidelines revision project. Whereas Radbruch et al. provide readers with a more critical appraisal of the quality of the current evidence base (e.g., focusing primarily on studies comparing two or more administration routes of the same opioid), this article s emphasis is specific to supporting clinical decision making. For general consistency, Tables 2 11 use a similar structure as in Radbruch et al. Methodology This review was based on human studies found in PubMed using the search terms describing each drug delivery route and the term opioid. For drug delivery routes that are widely used for acute pain (e.g., intramuscular and intravenous [IV]), the search term palliative care was added. The reference lists of each article were also manually searched. Searches were limited to English-language research. This article examines parenteral, inhaled, oral and nasal transmucosal, transdermal, rectal, vaginal, and nonswallowed enteral routes of administration. Neuraxial drug delivery has been reviewed recently and so intrathecal and epidural opioid administration will not be included in this review [5]. Intraosseous administration has also been excluded given the variety of other viable, less invasive methods of medication administration available to clinicians. The review is limited to mu-agonist opioids as this is the class of opioids most commonly used in chronic pain management settings, including palliative care. Partial agonist-antagonists (e.g., butorphanol, pentazocine, and nalbuphine) and partial agonists (e.g., buprenorphine) are excluded from this review. Weak opioids (e.g., codeine) are also excluded from this review due to the broader selection of titratable and more potent opioids currently available. Detailed reviews of the relative potency literature and recommendations regarding opioid rotation (switching) have recently been published [6,7], and the reader is referred to these papers for an update on determining dose equivalencies and converting from one opioid to another. Results Our results are summarized in the following subsections, categorized according to clinical usefulness (i.e., Preferable Routes of Administration Given Preexisting Access; Preferable Routes of Administration Without Preexisting Intravenous or Enteral Access; Available Routes of Administration Given No Preexisting Access; Routes of Administration with Mixed Support; Routes of Administration With Little Support). Preferable Routes of Administration Given Preexisting Access Intravenous (IV) Medications The most common drugs used in palliative care for IV administration include morphine, hydromorphone, methadone, and fentanyl. Oxymorphone is also available for IV use and has become a more viable option in the palliative care population as recently released oral formulations allow transition from an IV to an oral regimen in hospitalized adult patients prior to discharge [8,9]; however, no studies regarding the prevalence of oxymorphone s use in the palliative care population were found. Use of meperidine is not recommended for longterm or hospice use because accumulation of its metabolite, normeperidine, can lead to central nervous system toxicity [10]. Several studies have documented the efficacy of the IV use of morphine in palliative care patients and are summarized in Table 2 [11 13]. A consensus guideline on the use of parenteral methadone has been published [14] though we were unable to identify clinical trials regarding the efficacy of this drug administered intravenously in this population. Of note, a recent consensus guideline recommends that a pretreatment and follow-up electrocardiogram be obtained to measure the corrected QT interval (QTc) when prescribing methadone due to the risk of arrhythmia associated with the drug [15]. Fentanyl and sufentanil have also been described as opioids administered IV to palliative care patients [16]; however, no clinical trials regarding the efficacy of these opioids in this population were identified. In our experience, the use of IV fentanyl appears to be gaining in popularity, whereas the use of sufentanil is rare. Although IV delivery of opioids is widely used in palliative care, few studies have been published regarding the 1130

4 Oral Opioid Alternatives in Palliative Care Table 1 Alternate routes to oral opioid administration Route Advantages Cautions/Notes Preferred routes of administration with preexisting access Intravenous Widely used and accepted by clinicians and patients Excellent choice for patients with permanent venous access, generalized edema, coagulation disorders, or poor peripheral circulation Can infuse large volumes of opioids Useful when local side effects limit SC delivery Enteral Morphine is compatible with enteral feedings at temperatures from 22 to 50 C Preferred routes of administration without preexisting access Subcutaneous Results in morphine levels equivalent to IV route Relative potency is equivalent to IV route Flexible Useful for patients who have IV access but are receiving incompatible medication or total parenteral nutrition via the IV route Availability of SC access sites is virtually unlimited Infections complications are less frequent and less severe than with the IV route Less visible and less restrictive than traditional IV pumps Infusion needle can remain in place up to a week; eliminates need for multiple injections Patient, caregiver, and clinician ease Available routes of administration without preexisting access Transdermal patches Ease of administration Extended duration of action (72 hours) Good patient compliance Painlessness As compared with oral morphine, transdermal fentanyl has been shown to produce less constipation, nausea/vomiting, and vertigo/somnolence Intranasal (excluding nebulized medications) Because of the highly vascularity of the nasal mucosa, opioid absorption can be extremely rapid from this route Convenient Ease of administration Rapid onset of action No hepatic first-pass metabolism May have limited availability, especially in home/nursing home settings Can limit patient freedom/mobility Generally requires a higher level of patient and nursing involvement, training, and education Loss of ambulatory infusion equipment Infections Enteral drug practices vary widely leading to frequent medication errors, including crushing sustained-release tablets and failure to flush the tube before administering medication Generally only immediate-release dosage forms should be administered through an enteral feeding tube (see text for exceptions) Local complications are rare but can occur, especially in people with diabetes Infusion rates are a limiting factor; they should not exceed 5 ml/hour unless hyaluronidase is added to the infusion SC route should be avoided or used with caution in immunocompromised patients and in those patients with bleeding disorders Loss of ambulatory infusion equipment Local irritation can occur at patch site Contraindicated in opioid-naïve patients or in patients with acute or uncontrolled pain Should only be used in patients with stable pain because of the longer period of time required for titration Increased skin temperature increases absorption; patients/caregivers should be educated about the dangers of using heating blankets or other sources of heat Fevers may also increase absorption and can result in toxicity or increased pain after patch is depleted Patch must adhere properly to skin to ensure absorption Nasal congestion and local irritation Upper respiratory infection Change in nasociliary function Prevalence of the use of this route in palliative care or hospice settings has not been reported 1131

5 Kestenbaum et al. Table 1 Continued Route Advantages Cautions/Notes Routes of administration with mixed support in the literature Sublingual Simplicity Rapid onset of action for highly lipophilic drugs (e.g., fentanyl and methadone) Buccal Rectal Transdermal gels Simplicity Rapid onset of action for highly lipophilic drugs (e.g., fentanyl and methadone) Buccal fentanyl formulations are well studied and their efficacy, pharmacokinetics, and safety data are readily available Simplicity Useful in patients with nausea and vomiting or those with dysphagia, GI obstruction, malabsorption, or impaired neuromuscular function Ease of administration Painless Routes of administration with little support in the literature Intramuscular Readily available Clinician familiarity with route Vaginal Intranasal (Nebulized) Case reports indicate successful pain control with this route Convenience Ease of administration No hepatic first-pass metabolism Hydrophilic drugs such as morphine and hydrocodone are poorly absorbed sublingually Bitter taste and burning sensation possible Need to retain the drug sublingually for several minutes Studies have not provided compelling evidence for the effectiveness of morphine for rapid pain relief Case reports have described successful use of sublingual sufentanil, but no controlled studies have been performed Current products are intended for breakthrough pain in patients with cancer who are already receiving and who are tolerant to opioid therapy for their underlying persistent pain High unit price may make branded formulations prohibitively expensive in capitated reimbursement systems (e.g., hospice) No buccal formulations of morphine or oxycodone are available in the United States at this time Bioavailability can be affected by multiple factors, including the small surface area of the rectum, insufficient fluid to dissolve tablets or capsules, and presence of feces that can limit absorption Should not be used in patients with impaction, constipation, or diarrhea Should not be used if placement of the suppository will cause pain (e.g., inflamed hemorrhoids, fissures, or lesions of the anus or rectum) Avoid in patients with neutropenia or thrombocytopenia due to risk of bleeding or infection Avoid route if repeated dosing is necessary Not useful if patient or caregivers are unwilling or unable to accept or administer medications rectally Unclear evidence of absorption rates and bioavailability Difficulty in determining what constitutes a dose Can be surprisingly costly Painful May cause sterile abscesses and muscle fibrosis No pharmacokinetic advantage to other parenteral routes Variable absorption; wide variability in therapeutic blood levels Unnecessary given other, equally efficacious routes, e.g., SC Patient acceptability is varied Literature base is small Case reports only Nebulized route has not been well studied, and there is a lack of evidence for a clinical advantage over conventional routes of administration Previous findings suggest that bioavailability of nebulized morphine was low and that there was a risk of bronchospasm, especially at higher opioid doses; however, recent developments in inhalation delivery systems may provide more efficient delivery compared with early systems 1132

6 Oral Opioid Alternatives in Palliative Care Table 2 Selected studies of importance regarding intravenous opioid administration First Author, Year Study Design N Route(s) Studied Medications Studied Summary of Results and Additional Notes [2] De Conno, 2003 Retrospective chart review from 1987, 1993, and January October of 2000 [3] Hewitt, 2008 Prospective survey 164 children (age 0 19 years) with incurable cancer [11] Enting, 2002 Prospective 100 inpatients with [12] Mercadante, 2010 [13] Mazumdar, cancer patients Oral, SC bolus, SC continuous infusion, IV continuous infusion, spinal bolus, spinal continuous infusion, transdermal, intramuscular, rectal uncontrolled cancer pain or intolerable side effects 66 inpatients with breakthrough pain Retrospective 11 inpatients with severe cancer pain [17] Cherny, 1995 Prospective 100 inpatients with cancer pain [24] Fudin, 2000 Long-term stability of hydromorphone Oral, IV, SC, rectal, transdermal Morphine, methadone, fentanyl transdermal, oxycodone Morphine, diamorphine, fentanyl Parenteral (SC and IV) Morphine, fentanyl, sufentanil, hydromorphone IV, oral transmucosal, transdermal Morphine, methadone, oxycodone, buprenorphine, fentanyl, hydromorphone No patients received IV infusion in 1987 or 1993; 1% received IV infusion in Forty-two percent received opioids via the IV route in the last 6 months of their life, with a shift to IV use as death neared. Initiation of parenteral opioids led to a clinically important improvement at rest and during movement in 52% and 43% of patients, respectively, after 48 hours and in 71% of and 61% of patients after a median of 6 days. When using IV morphine in doses proportional to the basal opioid regimen for breakthrough pain, more than 97% and 90% of 368 episodes had a reduction of pain intensity of more than 33% and 50%, respectively. IV, oral Morphine None of the patients experienced Oral, IV, SC, intraspinal, transdermal Morphine, hydromorphone, fentanyl constipation with IV morphine when given for 1 to 4 days at a median dose of 36 mg/day (range, 12 mg/day to 108 mg/day). When converted to equianalgesic doses of oral morphine, 7 of the 11 patients experienced constipation and were prescribed laxatives. Eighteen percent of patients were discharged on IV opioids. IV Hydromorphone Twenty-eight-day stability of 10 mg/ml, 20 mg/ml, 50 mg/ml, and 100 mg/ml concentrations of hydromorphone in both 5% dextrose/water solution and 0.9% normal saline solution were confirmed by high performance liquid chromatography. 1133

7 Kestenbaum et al. Table 3 Selected studies of importance regarding subcutaneous opioid administration First Author, Year Study Design N Route(s) Studied Medications Studied Summary of Results and Additional Notes [36] Parsons, 2008 Retrospective review 515 patients, 545 injection sites [48] Fine, 2007 Guide for the clinical use of opioids [52] Pirrello, 2007 Retrospective chart review [144] Bruera, 1988 Randomized, crossover [55] Vanier, 1993 Randomized, double-blind, crossover [56] Watanabe, 2008 Randomized, double-blind, crossover SC Morphine, hydromorphone, oxycodone, codeine, methadone Oral, transdermal, rectal, transmucosal, buccal, sublingual, intramuscular, SC, IV, intraspinal Morphine, hydromorphone, oxycodone, oxymorphone, fentanyl 32 hospice patients SC Recombinant human hyaluronidase (for enhancement of medication infusion) 25 patients with advanced cancer 8 patients with severe cancer pain 12 patients with cancer pain [57] McDonald, 1991 Prospective 164 patients with severe cancer pain [58] Hunt, 1999 Randomized, double-blind, crossover SC Morphine, hydromorphone Oxycodone can be delivered via the SC route. Local skin reactions may occur with the SC route: 20% of sites in this study population developed redness. Parenteral oxycodone is not available in the United States at this time. Selection and initiation of opioid therapy is dependent on numerous factors, including patient characteristics (age, medical history), disease state, adverse reactions, and responsiveness to pain. Infusion rates of up to 500 ml/hour for bolus dosing and repeated dosing of up to 7 days were obtained. Analgesia and side effects were similar between the two delivery methods. SC Hydromorphone Although the two delivery methods resulted in similar pain intensity, patients who received the patient-controlled (intermittent) delivery required a lower mean hydromorphone dose than patients receiving continuous infusion. SC, by both continuous infusion (CSCI) and regularly scheduled intermittent injections (ISCI) Hydromorphone, morphine, oxycodone Analgesia and side effects were similar between the two delivery methods. SC Morphine Subcutaneous morphine provided effective analgesia with less severe nausea and vomiting in patients who did not achieve satisfactory pain relief with oral morphine. 23 hospice patients SC Morphine, Fentanyl Similar pain scores were observed with morphine and fentanyl but patients had more frequent bowel movements while receiving fentanyl. 1134

8 Oral Opioid Alternatives in Palliative Care Table 4 Selected studies of importance regarding transdermal opioid administration First Author, Year Study Design N Route(s) Studied Medications Studied Summary of Results and Additional Notes [60] Tassinari, 2009 Systematic literature review [61] Radbruch, 2000 Open, multicenter study, crossover design 13 studies Transdermal (as compared with oral morphine) 46 patients with chronic cancer pain Buprenorphine and fentanyl Oral, transdermal Morphine (oral), fentanyl (transdermal) Low-to-very low empirical support exists for the use of transdermal buprenorphine or fentanyl vs oral morphine in the treatment of cancer pain. The strength of recommendations for these transdermal opioids over oral morphine was weak. Transdermal fentanyl was associated with significantly less laxative use vs oral morphine. [62] Kornick, 2003 Review Transdermal Fentanyl Benefits cited include less adverse physical effects (e.g., constipation) than oral opioids; high patient satisfaction and tolerance; high utility in patients with swallowing or GI difficulties. Use is indicated for chronic pain unresponsive to other medications; it should not be used for acute and postoperative pain. Certain medical conditions can increase the likelihood of adverse effects, such as preexisting respiratory dysfunction leading to hypoventilation. Authors note that, prolonged elimination of transdermal fentanyl can become problematic if patients develop opioid-related adverse effects, especially hypoventilation. Additionally, adverse effects may take several hours to improve after patch removal. [63] Ackerman, 2004 Review of California Medicaid (Medi-Cal) claims data ( ) [64] Ahmedzai, 1997 Randomized, open, two-period, crossover [65] Wirz, 2009 Prospective, open-labeled, controlled [67] Zernikow, 2007 Systematic literature review 2,095 Transdermal Transdermal fentanyl as compared with oxycodone controlled-release 202 patients with cancer 174 outpatients with cancer 11 observational clinical or pharmacokinetic studies in children (there were no randomized or controlled cohort studies) Transdermal, oral Fentanyl (transdermal) as compared with morphine (sustained release, oral) Transdermal, oral Fentanyl (transdermal), buprenorphine (transdermal), hydromorphone (sustained release, oral) Risk of developing constipation was significantly lower among patients taking transdermal fentanyl. Fentanyl use was associated with less constipation and daytime sleepiness but poorer sleep than oral morphine use; patients reported a slightly higher preference for transdermal fentanyl than oral morphine. No difference was observed between transdermal and oral opioids in terms of gastrointestinal symptoms (nausea, emesis, and constipation). Transdermal Fentanyl Children may have a shorter elimination half-life and take longer to reach steady-state fentanyl serum concentrations than adults. Transdermal fentanyl in children appeared to produce less constipation and other side effects. The 72-hour dosing schedule recommended by the manufacturers may not be applicable to children because of poor patch adhesiveness; use of additional medical tape to ensure firm fixation of the fentanyl patch is suggested. Younger children may require higher doses referenced to body weight than older children or adults. As such, adequate medication should be provided during initiation to prevent breakthrough pain. 1135

9 Kestenbaum et al. Table 5 Selected studies of importance regarding intranasal opioid administration First Author, Year Study Design N Route(s) Studied Medications Studied Summary of Results and Additional Notes [69] Portenoy, 2010a Randomized, double-blind, placebo-controlled crossover 114 patients with cancer Intranasal, oral FPNS as compared with morphine (at least 60 mg) Fentanyl pectin nasal spray produced significantly better pain intensity scores than placebo in as early as 5 minutes after administration; significantly better summed pain intensity difference (SPID) scores from 10 minutes until 60 minutes; and significantly better pain relief scores from 10 minutes. More than 90% of episodes treated with FPNS did not require rescue medication compared with 80% of episodes treated with placebo. No problematic nasal effects occurred, and 87% of patients opted to continue receiving FPNS in a follow-on open label study. [70] Portenoy, 2010b Multicenter, open label 356 patients with cancer Intranasal FPNS The safety profile of FPNS was typical of that seen with other opioids and nasal assessments revealed no nasal toxicity. Rescue medication was not required for 94% of FPNS-treated episodes and more than 90% of patients did not require an increase in dose from their initial dose. [71] Taylor, 2010 Randomized, placebocontrolled, double-blind [79] Christrup, 2008 Randomized, double-blind, two-way, crossover [80] Fisher, 2010 Randomized, open label, crossover [81] Foster, 2008 Randomized, double-blind, double-dummy, crossover 114 patients with cancer Intranasal FPNS Only 6% of patients were unable to find an en effective dose of 42 patients undergoing molar extraction FPNS. FPNS produced significantly better pain intensity scores at 5 minutes than placebo (P < 0.05). At 10 minutes 33% of episodes had at least 2-point decrease in pain intensity (P < ). Patient satisfaction for convenience and ease of use was reported by 70% and 68% of patients, respectively, and 87% of patients continued treatment with FPNS after the study. Intranasal, IV Fentanyl There was no difference in onset and duration of pain relief or in pain 18 healthy adults Intranasal, oral Fentanyl (FPNS, fentanyl chitosan, and fentanyl in chitosan-poloxamer 188) as compared with oral transmucosal fentanyl citrate lozenge 24 patients undergoing molar extraction [82] Moksnes, 2008 Prospective 12 patients undergoing [83] Rickard, 2007 Prospective, randomized, open-label, controlled [84] Veldhorst- Janssen, 2010 Randomized, double-blind, controlled [85] Kaasa, 2010 Randomized, open-label, two-period, crossover [86] Kress, 2009 Phase III, double-blind, randomized, placebocontrolled, crossover [87] Mercadante, 2009 Randomized, open label, crossover transurethral resection of the prostate gland scores. Intranasal was associated with significantly less use of rescue medication. Intranasal formulations had significantly increased systemic exposure and reduced times to peak plasma values than the oral lozenge. Fentanyl pectin nasal spray demonstrated the most favorable tolerability. Intranasal, IV Fentanyl Rapid onset of intranasal fentanyl is helpful in acute episodes of breakthrough pain. Intranasal Fentanyl Arterial maximum serum concentration was significantly higher than 258 adult outpatients Intranasal, IV Fentanyl (intranasal) as compared with morphine (intravenous) 33 female patients who underwent breast reduction or augmentation venous. Arterial time to maximum serum concentration was 5 minutes shorter than venous. Authors object to the use of venous concentrations for the prediction of onset time of analgesia. No significant differences in pain reduction effectiveness, safety, and patient acceptability were reported. Intranasal Fentanyl There was a significant reduction in pain intensity with fentanyl vs saline placebo at 1 hour postsurgical drain removal; no difference in pain intensity at the time of drain removal was reported. 19 patients with cancer Intranasal Fentanyl Intranasal fentanyl demonstrated quick onset and was well tolerated in managing breakthrough pain. 120 patients with cancer Intranasal Fentanyl Intranasal fentanyl facilitated rapid onset of activity and was clinically effective in managing breakthrough pain. 139 patients with cancer Intranasal, oral transmucosal [145] Harlos, 2013 Retrospective chart review 11 newborns and infants undergoing palliative care Fentanyl Intranasal was associated with faster meaningful analgesia and greater patient preference than was oral transmucosal administration. Intranasal Fentanyl In all cases, fentanyl was well tolerated with no adverse events. 1136

10 Oral Opioid Alternatives in Palliative Care Table 6 Selected studies of importance regarding sublingual opioid administration Route(s) Studied Medications Studied Summary of Results and Additional Notes First Author, Year Study Design N Sublingual absorption of methadone at a ph of 6.5 was 34%. Sublingual absorption and bioavailability of morphine is poor; highly lipophilic medications demonstrate better bioavailability. Sublingual Methadone, fentanyl, buprenorphine, morphine [89] Weinberg, 1988 Observational healthy patients (n varied by test condition) 7 patients with cancer Sublingual Methadone Median time to analgesic onset and time to meaningful pain reduction occurred within 5 minutes of administration. Six of the seven patients asked to continue using sublingual methadone following the trial. [94] Hagen, 2007 Open label, feasibility [95] Hagen, 2010 Feasibility 9 patients with cancer Sublingual Methadone Mean pain intensity dropped by 1.7 points (on a 10-point numerical scale) within 10 minutes of sublingual methadone administration, and by 3.2 points after 15 minutes. Sublingual Methadone Sublingual methadone appears to be a suitable alternative to IV and topical administration in the treatment of mucositis-related pain. [96] Gupta, 2010 Case study Male patient with mucositis-related pain prevalence of its use [2,3,17]. These studies show an increasing trend in its use and are summarized in Table 2. Indications The IV route is useful for patients who already have a permanent venous access device or who have generalized edema, coagulation disorders, or poor peripheral circulation [18]. It is also useful when a less invasive route is temporarily unavailable (e.g., prior to or following surgery), when large volumes of opioids are required [19,20], or when a patient experiences local side effects with subcutaneous (SC) delivery [18]. This route is useful if there is a need to titrate or adjust opioid dose due to rapidly changing pain levels [19,21], if a rapid response is required, if the patient is experiencing acute pain, or if excessive side effects such as nausea and vomiting occur with other routes. This route is often used short term for hospitalized patients who can be carefully monitored but can also be used by patients cared for at home by utilizing ambulatory infusion equipment. A study of parenteral morphine prescribing patterns in 50 inpatients with advanced cancer reported the major indications included uncontrolled pain (40 patients), nausea and vomiting (three patients), respiratory distress (one patient), and other (six patients) [22]. Advantages The primary advantages include ease of administration and dose regulation, rapid onset of pain relief, and high patient acceptability [23]. Cautions and Considerations There are several considerations for using the IV route. This route may have limited availability (especially in the home/nursing home setting) and can limit patient freedom/mobility. The IV route generally requires a higher level of patient and nursing involvement, training, and education [19]; and skilled nursing may be required if the patient/family is unable to care for a catheter. However, new technological developments are simplifying the use of the IV route in patients being cared for outside the hospital. In addition, peripherally inserted central catheter (PICC) lines and Mediports are proven semi-permanent IV solutions that can decrease or mitigate the amount of patient and nursing care that comes with traditional IV catheters. In general, the IV route, whether temporary or semipermanent, incurs higher costs than the SC route [24]. However, in some cases, the IV route may reduce costs. For example, a review of studies on the use of IV morphine for patients with uncontrolled pain found that use of IV morphine for titration was likely to reduce the length of hospital stay compared with the use of an oral titration strategy that might require several days or weeks to reach an effective dose [25]. Another cost consideration, particularly for hospice programs, relates to the potential for loss of ambulatory infusion equipment as a result of nonreturn. Although the rate of nonreturn will vary among hospices, even a small number of missing units can have a significant financial impact given a list price over US $3,000 for many of the typical pumps used in the United States at this time (A.O. Vilches, pers. comm., March 4, 2014). 1137

11 Kestenbaum et al. Table 7 Selected studies of importance regarding buccal opioid administration First Author, Year Study Design N Route(s) Studied Medications Studied Summary of Results and Additional Notes [104] Beyssac, 1998 Cross-over 12 healthy adults Buccal (30 mg oral controlled release tablet vs a 20 mg aqueous solution retained in the mouth for 10 minutes vs a 60 mg bioadhesive buccal tablet placed between the lower gum and lip for 6 hours) [105] Kokki, 2006 Randomized, open label [106] Kokki, 2004 Prospective, open 15 children aged 6 91 months undergoing inpatient surgery 40 healthy children, age 6 93 months, undergoing surgery Morphine The amount of morphine absorbed from the solution was very low, approximately 10% of the dose. Plasma morphine levels for the buccal tablet were similar to that of the oral controlled-release tablet with relative bioavailability of the buccal tablet estimated to be 98% compared with the controlled-release tablet. Buccal (parenteral liquid, 10 mg/ml) Oxycodone Cmax ranged from 5.4 to 39 ng/ml (median IV, intramuscular, buccal, or gastric administration (parenteral liquid, 10 mg/ml) 16 ng/ml) with 12 of the 15 children reaching the oxycodone analgesic concentration of 12 ng/ml, which was sustained for minutes (median 160 minutes). Tmax ranged from 30 to 120 minutes (median 60 minutes). Oxycodone Eleven children received buccal oxycodone. The peak drug concentration following buccal administration was (mean 9.8) mcg/l compared with (mean 82) mcg/l following IV administration. Time-to-peak concentration was (mean 221) minutes following buccal administration compared with 2 30 (mean 16) minutes following IV administration. The estimated bioavailability of buccal oxycodone was calculated to be (mean 0.55). 1138

12 Enteral Medications Liquid formulations of opioids can easily be used with enteral tubes (e.g., morphine, oxycodone, and hydromorphone). The extended release preparation of most opioids cannot be crushed and flushed down an enteral tube; however, formulations of pelletized or beadcontaining extended release morphine capsules have been studied and demonstrated benefits in pain reduction when opened and administered via 16-French gastrotomy tube [26,27], although further study in larger samples is suggested [27]. No articles describing the prevalence of use of this route of administration in palliative care patients were identified. Indications The enteral route of opioid administration may be warranted in patients who require placement of a gastrostomy tube or jejunostomy tube for nourishment, such as when an obstruction is present in the upper gastrointestinal (GI) tract [28] or for patients with grade III or IV mucositis [27]. This route may be particularly useful for children at the end of life who have a gastrostomy tube placed [29]. Advantages Enteral administration is a steady route in patients with preexisting access. It is considered a favorable alternative for patients who cannot tolerate other administration routes (e.g., parenteral and topical) [28,30]. Cautions and Considerations The most important caution is to avoid the use of crushed extended release products with enteral tubes. This negates the product s ability to deliver the opioid over the extended timeframe and can lead to unintended and dangerous increases in blood levels [31]. When using pelletized or bead-containing extended release morphine capsules, nasogastric administration should be avoided [26]. An in vitro study of the compatibility of oral morphine with enteral feeding products found that morphine is stable in enteral feedings at temperatures from 22 to 50 C [30]. In some situations, abuse has been reported by crushing extended release preparations and flushing them through enteral tubes. The authors acknowledge that even in a palliative care and hospice population, there remains the potential for abuse with any opioid given by any route. Health care practitioners and organizations should remain vigilant for this possibility and have appropriate policies and procedures in place to ensure such situations are handled appropriately and consistently. The introduction of several newer extended release formulations with sequestered anti-abuse agents may help [32], and various resources are available for clinicians to aid in risk reduction [33,34]. Preferable Routes of Administration Without Preexisting IV or Enteral Access Subcutaneous (SC) Medications Concentrated solutions of morphine or hydromorphone are the most commonly used opioids in Oral Opioid Alternatives in Palliative Care SC delivery [35 37]. Hydromorphone is a good alternative to morphine when higher doses are required (or when morphine metabolites become problematic) because it is more potent, allowing for lower infusion rates required by SC infusion [38,39]. Fentanyl, sufentanil, and alfentanil have also been delivered via this route [37,40 44] but are more expensive options. Methadone is occasionally delivered via this route [36,45] but may be limited due to its association with skin irritation, which may be reduced by rotating the infusion site every 1 2 days or using intermittent boluses vs continuous infusion [14,46]. A recent consensus guideline concluded that the methadone infusion rate should not exceed 2 3 ml/hour because a higher rate can cause infiltration of the methadone, local edema, and poor systemic uptake resulting in inadequate analgesia [14]. Furthermore, the instability of methadone may limit its use in home care settings [14]. Indications A survey of US hospices found that the most common indications for the use of continuous SC infusion were pharmacological management (95%), poor IV access (56%), no oral intake (38%), dehydration (8%), infusion of saline (2%), and nutrition (1%) [29]. Another study reported that indications for 52 patients who received intermittent SC injections of medications in their hospice were as follows: difficulty swallowing (48%), GI obstruction (4%), intractable pain (33%), nausea/vomiting (10%), patient/caregiver preference (21%), and necessity for rapid dosing (8%) [35]. Advantages The SC route has become a favored route of opioid administration in palliative care due to its flexibility, safety, and practicality. This route may be more acceptable to patients and their caregivers as it may be less restrictive and less visible than other routes. The SC route is particularly useful for patients with dysphagia, nausea and vomiting, or bowel obstruction [20,47]; in addition, the rate limited absorption of the SC route can be advantageous in that the risk of inadvertent overdose is reduced, which increases its safety in unsupervised settings. Cautions and Considerations Several factors should be considered when deciding whether to use the SC route for a patient. Although the infusion needle can remain in place for up to 1 week [47,48], this route may require more frequent site rotation than a central IV, but site changes can be easily accomplished. Whereas there may be limited peripheral venous access sites, availability of SC access sites is virtually unlimited [18]. Infectious complications are less frequent and less severe than with the IV route; local complications are rare but may occur, especially in patients with diabetes [49]. The SC route should be avoided or used with caution in immunocompromised patients and in those patients with bleeding disorders [50]. Numerous injection sites can be used for SC drug delivery including the abdomen, thigh, buttocks, and subclavicular areas [51]. Sites that interfere the least with the patient s 1139

13 Kestenbaum et al. mobility and are not easily accessible by patients should generally be selected. A retrospective study of 545 SC injection sites in 514 palliative inpatients found that the most common site locations were arm (61%), chest (17%), thigh (15%), abdomen (6%), and back (<1%) [36]. Local skin reactions may occur with the SC route with one study reporting that of 308 intermittent SC administrations 20% of sites developed redness. Of note, all patients were able to continue receiving SC opioids by changing the injection site. Reasons for site changes included redness (20%), bleeding (8%), leakage (5%), swelling (2%), pain (1%), and inadvertent removal (<1%). There was no significant difference among different anatomical locations for site duration and frequency of and type of side effects [36]. The volume of fluid that can be administered per hour is a limiting factor; Pirrello et al. [52] reported the nursing norm as 3 ml/hour and infusion rates should not exceed 5 ml/hour unless hyaluronidase is added to the infusion, in which case larger infusion rates can be utilized [48]. A study by Moulin et al. [53] reports that the mean bioavailability of continuous SC infusion of hydromorphone was 78% that of IV administration, though there was no reported differences in pain analgesia or symptom control. In 1984, Waldmann et al. [54] reported no significant difference in the rate of SC vs IV morphine absorption in a 24-hour period in patients being ventilated postoperatively. Table 3 provides a summary of the remaining literature regarding the SC route. Of particular importance, studies by Justad [51] and by Vanier et al., Watanabe et al., and McDonald et al. [55 57] compare continuous vs intermittent SC delivery, while Hunt et al. [58] found SC morphine to provide effective analgesia with less severe nausea and vomiting in patients who did not achieve satisfactory pain relief with oral morphine. Available Routes of Administration Given No Preexisting Access Transdermal Patches Medications Currently, the only approved transdermal opioids in the United States are fentanyl and buprenorphine. Advantages Transdermal fentanyl has been reported to be less constipating than oral morphine [59 64]. A recent meta-analysis of 32 cohort studies comparing transdermal fentanyl and oral morphine that included 2,651 patients found that compared with the oral morphine group, transdermal fentanyl produced less constipation, nausea/vomiting, and vertigo/somnolence [59]. Other studies that indicate both positive and negative findings of transdermal fentanyl [60 65] are included in Table 4. Cautions and Considerations One issue that has been noted with transdermal fentanyl is the wide variability in fentanyl absorption from the patch. Absorption and urinary excretion characteristics of fentanyl in palliative care patients were evaluated by analyzing nearly 500 patches for residual fentanyl content and determining fentanyl and norfentanyl levels in the urine of 50 patients [66]. Wide variability in estimated dose rate and delivery occurred with fentanyl delivery 8.5% higher for the 25 mcg/hour patch compared with the 75 mcg/hour patch. Fentanyl delivery was 7.5% higher when the patch was applied to the arm compared with the leg. Gender and type of cancer pathology accounted for 40% and 64% of the variability, respectively. Transdermal fentanyl also can be used in pediatric populations, with one study [67] concluding that children may take longer to reach steady-state fentanyl serum concentrations than adults, and younger children may require higher doses referenced to body weight than older children or adults. Further findings are included in Table 4. Intranasal Medications The intranasal route has been used in palliative care to administer several opioids including fentanyl, morphine, alfentanil, sufentanil, and oxycodone [68]. Intranasal opioid delivery involves administration of a solution into the nostril directly or via a spray device. Indications An intranasal fentanyl formulation that uses pectin as a penetration enhancer (fentanyl pectin nasal spray [FPNS]) is currently marketed in Europe and was recently approved in the United States. This formulation was designed to deliver fentanyl in a manner intended to match the characteristics of a breakthrough pain episode. Its efficacy, safety, and effectiveness in the treatment of breakthrough pain has been upheld [69 71]. Advantages The advantages of intranasal administration are similar to those of oral transmucosal delivery of opioids including convenience, ease of administration, rapid onset of effect, and no hepatic first-pass metabolism. Because of the high vascularity of the nasal mucosa, opioid absorption can be extremely rapid from this route [72]. Dale et al. [68] published a comprehensive review of pharmacokinetic studies of nasal administration of opioids, including fentanyl, alfentanil, sufentanil, and oxycodone. Overall, times to reach maximum blood concentrations ranged from 5 to 50 minutes, and bioavailability of the different opioids ranged from 46% to 71%. The authors noted considerable inter-individual variation in pharmacokinetics and clinical outcome, which they suggested may have been a result of lack of optimization of nasal formulations. They concluded that nasal opioid administration had potential utility but required more study. A more recent review reached a similar conclusion [73]. Cautions and Considerations Disadvantages of this route include the potential for side effects such as nasal congestion, nasal irritation, rhinitis, upper respiratory infection, sinus congestion, and local irritation [68]. Chronic opioid administration via the intranasal route has been suggested to lead to a change of nasociliary function [73]. The route may be noxious for some patients, particularly children [74]. However, a recent study of intranasal fentanyl used for acute analgesia found that the route was 1140

14 well tolerated and acceptable to children aged 1 3 years [75]. The maximum volume of intranasal opioids should not exceed 150 μl, which for some opioids may require a higher concentration than the IV preparation to reach the effective dose [76] As publication of these reviews show [68,73], considerable efforts have been undertaken to optimize delivery vehicles of intranasal opioids, particularly fentanyl. Of particular note, two recent reports [77,78] lend support for intranasal fentanyl as effective, safe, and well tolerated for managing breakthrough pain especially that of FPNS. Studies of different doses and formulations of intranasal fentanyl have been published in healthy volunteers [79 81] as well as studies of acute pain [82 84] and chronic pain [69 71,85 87]; these are summarized in Table 5. Routes of Administration with Mixed Support Oral Transmucosal (Sublingual and Buccal) In the mouth, transmucosal drug delivery can occur across gingival, sublingual, or buccal tissues. The most studied and used in clinical care are the latter two. The rate-limiting factor affecting absorption is the physiochemical characteristics of the drug, especially ionization and oil vs water solubility (i.e., lipophilicity and hydrophilicity). Sublingual Medications Though used frequently in the hospice setting specifically [88], the prevalence of sublingual opioid administration for pain control in nonhospice palliative care settings at large has not been reported, but case series data suggest that use in the nonhospice palliative care populations is rare. Drugs that are highly lipophilic, such as fentanyl and methadone, are well absorbed sublingually. Hydrophilic drugs such as morphine and hydrocodone are poorly absorbed; thus, most of the efficacy of sublingually administered hydrophilic opioids results from the drug being swallowed [89 91]. In the United States, a sublingual formulation of fentanyl has been recently approved for the treatment of breakthrough pain in opioid tolerant cancer patients, with very similar pharmacokinetic and pharmacodynamic characteristics as other transmucosal fentanyl formulations with the same indications [92,93]. Indications Sublingual use of lipophilic opioids is indicated for patients who cannot swallow, but the routine use of sublingual hydrophilic opioids, such as morphine, is not supported by the literature. Advantages Advantages of this route include its simplicity to administer. Feasibility studies of sublingual methadone appear promising, including favorable reports of safety, effectiveness, and patient tolerance [89,94 96] (Table 6). Radbruch et al. report more rapid onset and more significant pain relief from sublingual administration than from rectal or oral routes. Case reports have described the successful use of sublingual sufentanil [97,98]; however, no controlled studies have been performed. Cautions and Considerations Disadvantages of this route include bitter taste, burning sensation, possible ulceration, and need to retain the drug sublingually for several minutes [16,89 91,99]. Patients are required to avoid eating or drinking until the medication has been completely dissolved. Coluzzi [99] published a thorough review of studies that evaluated sublingual delivery of morphine and concluded that clinical data did not provide compelling evidence for the effectiveness of sublingual morphine for rapid pain relief. Pharmacokinetic data indicated that blood levels of morphine following sublingual administration do not rise faster than those following oral administration. In a more recent review, Reisfield & Wilson [90] supported the conclusions of Coluzzi [99] regarding morphine and extended these conclusions to oxycodone and hydromorphone as well. No studies of the use of sublingual morphine in non-hospice palliative care patients were identified. Buccal Oral Opioid Alternatives in Palliative Care Medications Although the prevalence of use of the buccal route in palliative care has not been reported in the literature, the route is commonly used in this population. Currently, three formulations of buccal fentanyl are available: a lozenge on a handle (oral transmucosal fentanyl citrate [OTFC]), an effervescent fentanyl buccal tablet (FBT), and a fentanyl buccal soluble film (FBSF). OTFC incorporates fentanyl into a lozenge that is sucked, and FBT incorporates fentanyl into an effervescent tablet that is placed in the buccal cavity. FBSF is a film containing fentanyl that is placed on the buccal mucosa. These products are indicated for breakthrough pain in patients with cancer who are already receiving and who are tolerant to opioid therapy for their underlying persistent pain. Extensive research has been conducted on each of these products during their development prior to regulatory agency approval and in postmarketing surveillance. Thus, pharmacokinetics, efficacy, and safety data from transmucosal fentanyl product use are well described [ ]. Morphine and oxycodone have also been evaluated for buccal administration [ ], although no buccal formulations of these opioids are currently on the market in the United States. A few studies have examined this in both adults [104] and children [105,106]; details are included in Table 7. Indications As with sublingual administration, buccal use of lipophilic opioids is indicated for patients who cannot swallow, but the routine use of buccal hydrophilic opioids is not empirically supported. Advantages The advantages of this route are similar to that of the sublingual route including its simplicity to administer and rapid onset of action for highly lipophilic drugs, such as fentanyl. 1141