Send Orders for Reprints to [email protected] 124 Current Drug Targets, 2014, 15, 124-135 / in the Management of Patients with Pain and –Induced Bowel Dysfunction

Wojciech Leppert*

Chair and Department of Palliative Medicine, Poznan University of Medical Sciences, Poznan, Poland

Abstract: Introduction: Common adverse effects include opioid–induced bowel dysfunction (OIBD), which comprises opioid–induced , dry mouth, nausea, vomiting, gastric stasis, bloating, and abdominal pain. Tradi- tional which are often prescribed for the prevention and treatment of OIBD possess limited efficacy and display adverse effects. A targeted approach to OIBD management is the use of a combination of an opioid agonist with antagonist or administration of purely peripherally acting opioid receptor antagonists. Methods: A literature search with terms “oxycodone/naloxone” in the PubMed and MEDLINE database updated on 31st July 2013. All studies of oxycodone/naloxone (randomized, controlled trials and open, uncontrolled studies) were in- cluded. In addition, studies on and pharmacodynamics of oxycodone/naloxone were included. Results: A combination of prolonged–release oxycodone with prolonged–release naloxone (OXN) in one tablet with a fixed 2:1 ratio provides effective analgesia with limited disturbing effect on bowel function. Oxycodone is a valued opioid administered either as the first strong opioid or when other strong opioids have been ineffective. Naloxone is an opioid re- ceptor antagonist that displays local antagonist effect on opioid receptors in the gastrointestinal tract and is nearly com- pletely inactivated in the liver after oral administration. As demonstrated in controlled studies conducted in patients with chronic non–malignant and cancer–related pain OXN in daily doses up to 80 mg/40 mg provided equally effective analge- sia with an improved bowel function compared to oxycodone administered alone. Conclusion: OXN is an important drug for chronic pain management, prevention and treatment of OIBD. Keywords: Opioid–induced bowel dysfunction, opioid–induced constipation, opioid receptor antagonists, oxy- codone/naloxone, pain.

INTRODUCTION At each step of the WHO ladder non–opioids, Opioid–Induced Bowel Dysfunction weak opioids ( for mild–to–moderate pain) and strong opioids (opioids for moderate–to–severe pain inten- Pain treatment is based on the analgesic ladder estab- sity) are accompanied by adjuvant analgesics (co–analgesics) lished in 1986 by the World Health Organization (WHO) [1]. with the aim of enhancing opioid analgesia (e.g. bisphospho- In most patients, pain is successfully relieved through the use nates in bone pain, anticonvulsants, antidepressants, local of opioids alone or in combination with adjuvant analgesics anesthetics, and NMDA receptor antagonists in neuropathic in accordance with the WHO analgesic ladder. Cancer pain pain) [4, 5]. The use of an analgesic ladder should be indi- management guidelines have been recently updated by the EAPC (European Association for Palliative Care) [2]. Mor- vidualized, with the appropriate application of supportive phine along with oxycodone and adminis- drugs (e.g. laxatives and antiemetics) for the prevention and tered orally are recommended as the first choice opioids at treatment of opioid adverse effects [6] and non– the 3rd step of the WHO analgesic ladder, which also com- pharmacological measures, such as radiotherapy and inva- prises additional opioids (transdermal formulations of fen- sive procedures (nerve blockades and neurolytic blocks) [7]. tanyl and , and tepentadol) for the One of the common opioid adverse effects is a group of treatment of cancer patients with moderate–to–severe pain symptoms associated with the opioid influence on gastroin- intensity. Currently, instead of weak opioids, it is possible to testinal tract function, the so called opioid–induced bowel use low doses of strong opioids (opioids for moderate–to– dysfunction (OIBD). These symptoms reflex a complex im- severe pain: up to 30 mg, oxycodone up to 20 mg pact of opioids on gastrointestinal tract (Table 1). Symptoms and hydromorphone up to 4 mg per day, administered by the of OIBD comprise not only opioid–induced constipation oral route) on the second step of the WHO analgesic ladder (OIC), but also dry mouth, gastro–esophageal reflux–related [3]. symptoms (heartburn), nausea, vomiting, chronic abdominal

pain, bloating, constipation–related symptoms: straining, *Address correspondence to this author at the Chair and Department of hard stools, painful, infrequent and incomplete bowel Palliative Medicine, Poznan University of Medical Sciences, Osiedle Rusa 25 A, 61 – 245 Poznan, Poland; Tel/Fax: + 48 61 8738 303; movements, and diarrhea–related symptoms: urgency, loose E–mail: [email protected] bowel movements and frequent bowel movements [8].

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Table 1. Pharmacological Mechanisms and Clinical Symp- erance to the constipating effect of opioids does not develop. toms of Opioid–Induced Bowel Dysfunction, OIBD is often unsuccessfully managed due to not only the Adapted from [8]. lack of efficacy and adverse effects of traditional laxatives, but also due to the lack of attention and expertise of the medical staff [15]. Another approach is a switch from oral or Pharmacological Mechanisms Clinical Symptoms parenteral to transdermal route of opioid administration. However, all opioids display OIBD including transdermal Decreased saliva production Xerostomia formulations [16].

Dysmotility of the lower Gastro–esophageal reflux TARGETED TREATMENT OF OPIOID–INDUCED esophageal sphincter (or, rarely, dysphagia) BOWEL DYSFUNCTION Decreased gastric secretion, Delayed absorption of medication, Newer strategies for the management of OIBD include emptying and motility upper abdominal discomfort administration of a combination of prolonged–release (PR) Disturbed fluid secretion and oxycodone with PR naloxone (OXN) tablets and purely pe- Constipation absorption ripherally acting –opioid receptor antagonists, namely methylnaltrexone [17]. Abnormal bowel motility, in- creased resting contractile tone in Straining, incomplete bowel OXYCODONE COMBINED WITH NALOXONE the small and large intestinal evacuation, bloating, abdominal circular muscles and sphincter distension, constipation Pharmacodynamics dysfunction One of the methods to decrease the frequency and sever- Increased amplitudes of Spasm, abdominal cramps and ity of OIBD in patients requiring strong opioids is to use a non–propulsive segmental bowel pain, stasis of luminal contents and formulation composed of an opioid and opioid receptor an- contractions hard dry stool tagonist. Oxycodone is semisynthetic derivative, an opioid of the step 3 WHO analgesic ladder that binds to pre- Biliary colic, epigastric discomfort Constriction of sphincter of Oddi dominantly and opioid receptors [18]. Naloxone is a and pain semisynthetic morphine derivative an that acts at , and opioid receptors. As naloxone has a very Increased anal sphincter tone and high affinity to opioid receptors, it displaces opioid agonists impaired reflex relaxation during Evacuation disorders from the receptors and is commonly administered by the rectal distension parenteral route for the treatment of . How- Diminished intestinal, pancreatic ever, when administered by the oral route, naloxone im- Hard, dry stools and biliary secretion proves bowel function in patients with OIC [19].

Abnormal bowel motility, The oral formulation of OXN (Fig. 1) consists of PR increased fermentation and meteo- Chronic visceral pain oxycodone and PR naloxone. OXN tablets have different rism, opioid–induced hyperalgesia strengths: 5/2.5 mg, 10/5 mg, 20/10 mg and 40/20 mg. The optimal 2:1 ratio of OXN tablets was demonstrated in a Central effects of opioids Nausea and vomiting, anorexia phase II study, rendering effective analgesia and improve- ment in bowel function [20] with good treatment toleration The complex assessment of patients with symptoms of in patients with severe chronic pain [21]. OXN is registered OIBD is necessary for the application of effective treatment. for the indication of severe pain which may only be success- Several subjective scales were developed for that purpose, fully treated with opioid analgesics [22]. Thus, the indication i.e. the Bowel Function Index (BFI) [9], the Patient Assess- for the OXN administration is severe pain demanding strong ment of Constipation: the symptom questionnaire (PAC– opioid administration. Naloxone as an opioid receptor an- SYM) [10] and the quality of life questionnaire (PAC–QoL) tagonist counteracts OIC development by blocking the oxy- [11]. The objective assessment comprises the Bristol Stool codone activation of predominantly opioid receptors lo- Chart – a simple and easy to use method of objective as- cated in the myenteric and submucosal plexus in the gut wall sessment detecting stool frequency and stool consistency. while oxycodone provides analgesia [23]. OXN provides However, only a moderate correlation between stool form analgesia with limited effect of oxycodone on bowel func- and whole–gut or colonic transit time can be demonstrated tion. [12]. Other investigations comprise plain radiography, transit HO time studies, manometry, and anorectal dysfunction tests. O However, apart from plain radiography, these investigations CH3 are rarely used in patients with advanced diseases [13]. O O OH Numerous laxatives are prescribed for the prevention and N N treatment of OIBD, particularly for constipation–related CH3 OH O symptoms. Nonetheless, they possess limited efficacy and O display their own adverse effects [14]. Moreover, treatment with laxatives should be limited to a short period of time. Oxycodone Naloxone

Still, in patients with chronic non–malignant and cancer pain, they usually have to be taken for the long–term as tol- Fig. (1). Chemical structure of oxycodone and naloxone. 126 Current Drug Targets, 2014, Vol. 15, No. 1 Wojciech Leppert

Table 2. OXN Comparative Studies [20, 21, 31, 32, 35, 40, 44, 47, 48]

Author Patients Random- Duration of the [Reference Number] ized (Completed Daily Doses Double-Blind Analgesic Efficacy Adverse Effects Study Design the Study) Phase (days)

Meissner et al. [20] Gr. 1: 50 Gr. 1: OXY Good, comparable analgesia in all Comparable in all groups, no with- rand,db, parallel, (44) 40–80 mg + 28 groups. Better BFI scores with NAL 20 drawal symptoms observed. non–cancer (97.5%) Gr. 2: placebo mg and 40 mg vs. placebo (p < 0.05) The incidence of diarrhea increased and cancer pain 51 Gr. 2: OXY and stool frequency (NAL 40 mg vs. with an increase of NAL dose: 12.0%, (2.5%) (41) 40–80 mg + placebo; p = 0.001) with increasing 19.6%, 23.5% and 36% for placebo, Gr. 3: NAL 10 mg NAL doses. NAL 10 mg, 20 mg and 40 mg, respec- 51 Gr. 3: OXY BFI scores decreased as NAL dose tively; (42) 40–80 mg + increased – the best results OXY:NAL For OXY/NAL 1.5:1 ratio 50%, for 2:1 Gr. 4: NAL 20 mg ratio 1:1, 1.5:1 and 2:1); ratio 2:1 ratio 29.4% pts with diarrhea. 50 Gr. 4: OXY 40– deemed as optimal. (39) 80 mg + NAL 40 mg

Gr. 1: 50 Gr. 1: OXY Efficacy (pts): good or very good Tolerability (pts): good or very good Nadstawek et al. [21] (44) 40–80 mg + 28 43.5%, 50.0%, 67.4%, and 72.5% for 71.7%, 83.3%, 79.1%, and 82.5% for rand, db, parallel, Gr. 2: placebo placebo, NAL 10 mg, 20 mg, and 40 placebo, NAL 10 mg, 20 mg and 40 mg, non–cancer (97.5%) 51 Gr. 2: OXY mg, respectively. respectively. and cancer–related (41) 40–80 mg + Efficacy (inv): good or very good Tolerability (inv): good or very good pain (2.5%) Gr. 3: NAL 10 mg 47.8%, 54.8%, 67.4%, and 70.0% for 78.3%, 83.3%, 79.1%, and 85.0% for 51 Gr. 3: OXY 40– placebo, NAL 10 mg, 20 mg, and 40 placebo, NAL 10 mg, 20 mg and 40 mg, (42) 80 mg + NAL 20 mg, respectively. respectively. Gr. 4: mg Efficacy good or very good of The number of AE increased with an 50 Gr. 4: OXY 40– OXY/NAL 2:1 and placebo: 70.4% of increase of NAL dose: 111, 119, 129 (39) 80 mg + NAL 40 pts and inv, 43.5% pts and 47.8% inv, and 140 events for placebo, NAL 10 mg respectively. mg, 20 mg and 40 mg, respectively. Tolerability good or very good of The most frequent AE: sweating, diar- OXY/NAL 2:1 and placebo: 81.5% of rhea, nausea, abdominal pain, restless- pts and inv, 71.7% pts and 78.3% inv, ness, muscle cramps, sedation, head- respectively. ache and vertigo.

OXN: Significantly better and comparable Significant improvement in sleep (BPI– Vondrackova et al. OXN 154 (136) 20/10–40/20 mg 84 analgesia (BPI – SF, average pain) in SF) in both OXN and OXY groups over [31] OXY 151 (133) OXY: both OXN and OXY group over pla- placebo (p = 0.006 and p = 0.03, respec- rand, db, parallel, Placebo 20–40 mg cebo (p = 0.04 and p = 0.008, respec- tively). No withdrawal symptoms in all non–cancer pain 158 Placebo tively). groups. The most frequent AE: consti- (133) IR OXY Higher use of rescue analgesics in pation (8.4%: OXY 11.9%, OXN 8.4%, rescue analgesic placebo than in OXN (p = 0.0004) and placebo 5.1%), nausea (7.1%), head- 1/4 of daily dose OXY (p < 0.0001) group. ache (4.8%), vomiting (4.3%) and as required up to Better bowel function (BFI, CSBM) in diarrhea (4.1%: OXY 2.6%, OXN 4–6 h OXN than in OXY group. 5.2%, placebo 4.4%).

Good and comparable analgesia (NRS) Incidence of AE similar in both groups. Simpson et al. [32] OXN 162 (144) OXN: 84 and pain interference (BPI–SF) in both GI symptoms less frequent in OXN rand, db, parallel, OXY 160 (133) 20/10–50/25 mg OXN and OXY group; similar use of (19.4% pts) than OXY (29.6% pts): non–cancer pain and OXY: rescue analgesics in OXN and OXY constipation (2.8%: OXN 0.6%, OXY OIC 20–50 mg group. 4.9%) diarrhea (6.2%: OXN 5.6%, Improvement in constipation in OXN OXY 6.8%), nausea (8.4%: OXN 6.3%, better than OXY (BFI –15.2; p < OXY 10.5%), vomiting (2.8%: OXN: 0.0001, PACOI 1.3%, OXY 4.3%). –3.54; p < 0.0001, CSBM 1.66; p < 0.0001), less OXN (49 pts) than OXY (87 pts) took laxatives (p < 0.0001).

Oxycodone/Naloxone in Pain Management and OIBD Current Drug Targets, 2014, Vol. 15, No. 1 127

(Table 2) contd….

Author Patients Random- Duration of the [Reference Number] ized (Completed Daily Doses Double-Blind Analgesic Efficacy Adverse Effects Study Design the Study) Phase (days)

Good and comparable analgesia (NRS) More pts with AE in OXN (37.7%) than Löwenstein et al. OXN 130 (108) OXN: 84 in OXN and OXY group; similar and in OXY (29.6%) group. Opioid with- [35] OXY 135 (114) 60/30–120/60 mg low use of rescue analgesics in OXN drawal symptoms observed in 4 pts in rand, db, parallel, OXY: and OXY. OXY group. GI symptoms more fre- non–cancer pain and 60–120 mg Improvement in constipation in OXN quent in OXN pts (23.8%) than in OXY OIC better than in OXY (BFI –14.9; p < pts (16.3%): abdominal pain (7.7%, 0.0001, PAC–SYM, CSBM, BSFS); 1.5%), constipation (0.8%, 1.5%) diar- fewer pts receiving OXN (43.1%) than rhea (4.6%, 3.0%), nausea (10.0%, OXY (63.7%) took laxatives (p = 6.7%), vomiting (3.1%, 0.7%), respec- 0.0009). tively.

OXN: OXN rendered significantly lower Comparable in both groups, including Cloutier et al. [40] OXN 39 (33) 20/10–80/40 mg 28 each, mean VAS scores (48.6 ± 23.1 mm vs. bowel function (similar BFI scores). db, crossov, non– Placebo Placebo 2–7 wash–out 55.9 ± 25.4 mm; p = 0.0296) and mean No withdrawal symptoms (similar cancer pain and OIC 44 before study 5 – point pain intensity scores (2.1 ± modified SOWS scores) in any of the (35) Acetamino- initiation 0.8 vs. 2.4 ± 0.9; p = 0.0415), better group observed. phen/ sleep (p = 0.0046) and less rescue More somnolence (p = 0.045) in OXN 300 mg/30 mg analgesics (p = 0.0003) group rescue analgesic than placebo. as required (1 – 2 Pts and inv both preferred OXN over tablets up to placebo. A total 79% of pts chose to every continue OXN in a 6–month open– 4–6 h) label study

OXN: Good, comparable analgesia (BPI–SF) Ahmedzai et al. [44] OXN 92 (66) Mean 46.59 ± 28 and QoL (EORTC QLQ –C30 and Comparable in both groups, mostly GI rand, db, parallel, OXY 92 (67) 22.58 mg EQ–5D) in both groups. disorders. cancer–related pain (range 20/10 – Better bowel function (BFI; p < 0.01, No withdrawal symptoms in both with OIC 120/60 mg) PAC–SYM; groups. OXY: p = 0.014, EORTC QLQ –C30 consti- Less constipation in OXN group. Mean 43.09 ± pation scale) in OXN group. 19.31 mg (range 20–120 mg)

Pts < 65 years: 3 (day 1 was 48 OXN rendered similar analgesia to Comparable in both groups (51% of pts Kuusniemi et al. [47] OXN 70 (63) OXN: h after surgery) OXY as measured by the NRS: aver- at each group experienced AE but none db, parallel, post– OXY 20/10 mg age 24–h, current and worst pain inten- was serious). operative pain after 67 OXY: 20 mg sity scores (for all at rest and on move- The most frequent AE in both pts knee arthro–plasty (64) Pts = or > 65 ment). groups: constipation, nausea, vomiting years: Rescue analgesics were taken by 79% and insomnia. OXN: pts from OXN group and 73% pts from 10/5 mg OXY group. OXY: 10 mg* IR OXY 5 mg rescue analgesic

OXN: 3 OXN rendered similar analgesia to Comparable in both groups with no Comelon et al. [48] OXN 56 (40) 10/5 mg (the first dose 1– OXY as measured by the NRS with case of strong sedation or respiratory db, parallel, post– OXY OXY: 2 h before sur- similar use of rescue analgesics for depression. operative pain after 53 10 mg (single gery breakthrough pain. hystere–ctomy (45) doses) No difference in bowel function (BFI, iv OXY (0.003 BSFS). mg/kg via PCA) or IR OXY 5 mg rescue analgesics * Single doses of OXN and OXY. Both analgesics were administered twice daily (on day 1 and on day 2) and once daily on day 3. The first doses of both study drugs were given 60 minutes prior to epidural analgesia completion

128 Current Drug Targets, 2014, Vol. 15, No. 1 Wojciech Leppert

Analgesic effect of oxycodone is not reversed by naloxone depends on normal liver function, thus any hepatic naloxone and no symptoms of opioid withdrawal are ob- impairment should be carefully considered; in patients suf- served during the treatment with OXN. There is a clinically fering from liver failure, OXN administration is not recom- observed difference between the administration of immedi- mended [27]. ate–release (IR) and PR formulations of naloxone. IR The single–dose and multiple–dose pharmacokinetics of naloxone in some patients may attenuate analgesia or induce OXN vs. separate formulations of PR oxycodone and PR opioid withdrawal symptoms [24]. The PR naloxone formu- naloxone were evaluated in healthy adult subjects [28]. Both lation prevents the saturation of hepatic enzyme system re- were open–label, randomized, cross–over studies. In the sin- sponsible for naloxone metabolism and reduces the risk of gle dose study OXN (4 x 10/5 mg, 2 x 20/10 mg or 1 x 40/20 opioid antagonism in the CNS [18]. Contraindications for mg) or PR oxycodone 40 mg + PR naloxone 20 mg were OXN administration comprise bowel obstruction, acute ab- given in separate formulations. The single–dose study in- dominal conditions, diarrhea, allergy to the drug and hepatic cluded 28 subjects (22 men and 6 women, mean age 32.3 ± failure. OXN should not be administered before and 12 – 24 5.4 years). The mean plasma oxycodone concentration–time h after surgery. As no data exist for the administration of curves for OXN and PR oxycodone + PR naloxone were OXN in children and teenagers under 18 the drug should not similar. No significant differences between the treatments be administered in these patients [25]. were found and the 90% confidence intervals were within the In an exploratory study conducted among 15 healthy vol- range of bioequivalence. The findings of the single–dose unteers, the addition of PR naloxone to PR oxycodone de- study suggest that the pharmacokinetic properties of OXN creased the impact of PR oxycodone on bowel function [26]. are similar to those of PR oxycodone + PR naloxone admin- In fact, oxycodone PR 20 mg significantly extended colon istered in separate formulations. arrival time compared to placebo (7.19 vs. 5.15 h; p = In the multiple–dose study, subjects were assigned to one 0.0159). However, the addition of PR naloxone reduced the of 3 groups: OXN 40/20 mg, PR oxycodone 40 mg or PR oxycodone–induced prolongation of GI transit time, with naloxone 20 mg. This bioequivalence study included 34 sub- similar mean colon arrival time for the OXN 20 mg/10 mg jects (28 men and 6 women, mean age 36.0 ± 9.4 years). No (5.16 h) and placebo, although the difference between OXN differences were found between treatments with the excep- and PR oxycodone 20 mg was not significant (p = 0.0653). tion of minimal levels of NAL–3–G at steady state. The re- OXN 10 mg/5 mg had no significant effect, although OXN sults of the multiple–dose steady–state bioequivalence study in the dose of 20 mg/10 mg significantly reduced mean colo- suggest the same results of multiple administration of OXN, nic transit time by 2.1 h (p = 0.0376). PR oxycodone and PR naloxone as in the single–dose study. The pharmacokinetic properties of PR oxycodone were not Pharmacokinetics influenced by administering PR oxycodone in a combination Orally administered oxycodone displays high bioavail- product and the bioavailability of NAL–3–G from OXN was ability (60–87%) and is metabolized primarily in the liver similar to that of PR naloxone. These data suggest that the and in the intestine wall mainly to (through co–administration of PR oxycodone and PR naloxone in a CYP3A4) and to less extent to (via CYP2D6). combined formulation does not significantly affect bioavail- Oxycodone and its metabolites are excreted with urine and ability of either of its compounds. with faeces [23]. The volume of distribution of oxycodone Although highly fat meals may increase oxycodone equals 2 – 3 l/kg. The maximum plasma concentration is bioavailability this effect is clinically irrelevant. However, reached within 25 min after intravenous injection, 1.3 h after food does not affect NAL–3–G levels and OXN may be ad- IR administration and 2.6 h after administration of a CR ministered in fasting condition or with food. OXN was not formulation. The T1/2 (half–life) is approximately 2 – 3 h studied in patients during pregnancy and delivery. However, after intravenous administration, 3 h after administration oxycodone and naloxone penetrate to placenta and their with an IR and approximately 5 h after treatment with PR long–term administration in pregnant women may evoke oxycodone tablets. Oxycodone predominantly binds to al- opioid withdrawal syndrome in neonates. Oxycodone perme- bumin (45%) [18]. ates to the milk, thus OXN should not be administered in Naloxone exhibits low bioavailability after oral admini- lactating women [25]. stration (< 3%) and undergoes extensive first–pass metabo- As oxycodone is metabolized through P–450 system, es- lism in the liver, with the formation of naloxone–3– pecially CYP3A4 and CYP2D6, drugs inhibiting these en- glucuronide (NAL–3–G) predominantly. Another naloxone zymes, notably CYP3A4, should be avoided as they may metabolic pathway is N–dealkylation and reduction of the 6– increase oxycodone plasma levels and lead to toxicity [23]; keto group to 6– alpha– and 6–beta–naloxol although this especially refers to concurrent administration of only the latter has been detected in humans [25]. NAL–3–G CYP2D6 and CYP3A4 inhibitors [29]. As naloxone is me- is measured in plasma instead of parent compound which is tabolized through glucuronidation, the risk of drug interac- undetectable after oral administration. The maximum plasma tions is lower. concentration of NAL–3–G is reached within 60 min after oral naloxone administration. The T1/2 of naloxone is ap- Dosing Recommendations proximately 60 min after intravenous administration and that The starting OXN doses in opioid–naive patients are of NAL–3–G is approximately 8 h after oral administration 5/2.5 mg – 10/5 mg b.i.d. In patients not responding to weak of PR naloxone tablets. Naloxone and its metabolites are opioids (opioids for mild-to-moderate pain such as , excreted with urine. The effect of orally administered codeine and ) an initial dose of 10/5 mg or Oxycodone/Naloxone in Pain Management and OIBD Current Drug Targets, 2014, Vol. 15, No. 1 129

20/10 mg b.i.d. is usually effective. The initial dose should tively) and discontinuation rate due to AE (4.8% and 6.4%, be titrated to achieve effective analgesia and acceptable ad- respectively) was found in a combined analysis of two con- verse effects. The maximal daily dose of OXN that is rec- trolled studies [32, 35] conducted in patients with chronic ommended equals to 40 mg/20 mg twice daily. However, non–malignant pain [37]. some studies explored higher daily doses up to 120 mg/60 Controlled studies did not demonstrate an increased inci- mg. In case higher doses are required, oxycodone or other strong opioids in the appropriate doses should be considered. dence of opioid withdrawal syndrome during treatment with OXN in daily dose range of up to 120 mg/60 mg comparing When rotating from other opioids for moderate–to– to oxycodone [35]. This has also been the case in open stud- severe pain to OXN, the starting dose is established indi- ies, where opioid withdrawal symptoms were experienced by vidually, depending on the amount of previously adminis- 0.53% of patients in long–term study [36]. However, single tered opioid, analgesia, adverse effects and complex clinical cases report such possibility during treatment with high evaluation. During treatment with OXN patients should be OXN doses (240 mg/120 mg) [38] and patients with portal provided with constant access to IR formulations of opioids vein thrombosis [39]. for the management of breakthrough pain episodes. In case of IR oxycodone administration for this purpose the single OVERVIEW OF OXYCODONE/NALOXONE CLINI- th dose usually equals to approximately 1/6 of the daily oxy- CAL STUDIES codone dose used in OXN [25]. However, it should be kept in mind that when using IR opioids for breakthrough pain Patients with Chronic Non–Malignant Pain management, especially rapid acting formulations, Meissner et al. [20] reported a randomized, double–blind the dose should be individualized starting with the lowest study that assessed analgesic efficacy and impact on the OIC recommended dose and titrated to achieve good analgesia of OXN, and identified the optimal dose ratio of oxycodone and acceptable toxicity [30]. and naloxone. Two hundred and two patients with chronic In patients with mild hepatic impairment caution is ad- pain (most non–malignant, 2.5% cancer–related pain) and a vised and in subjects with moderate to severe hepatic im- stable oxycodone dose (40, 60 or 80 mg per day) were ran- pairment OXN is contraindicated [25]. OXN should be ad- domized into groups that received per day 10, 20, and 40 mg ministered with caution in patients with renal impairment; in of naloxone or placebo. After 4 weeks of the maintenance patients with severe renal impairment a switch to fentanyl or phase, patients received PR oxycodone for two weeks. Pain buprenorphine may be considered [3]. As OXN is contained intensity was evaluated by the NRS, and bowel function was in PR formulations the whole tablets should be swallowed assessed by the BFI. No loss of analgesia with PR naloxone without crushing, gnawing or chewing [18]. was observed. Bowel function improved with increasing PR naloxone dose. At pre–randomization, average scores of Adverse Effects 48.0, 52.8, 49.4 and 46.2 were observed for placebo, in the 10 mg, 20 mg and 40 mg PR naloxone groups, respectively, Generally, OXN is well–tolerated with mild or moderate and at the end of maintenance the equivalent scores were intensity of adverse events (AE) in most patients. AE of 45.4, 40.3, 31.3 and 26.1 (p < 0.05 for 20 mg and 40 mg PR OXN and PR oxycodone are similar. The frequency of diar- naloxone vs. placebo). In a quadratic response surface model rhea was slightly higher in OXN comparing to PR oxy- with PR naloxone and PR oxycodone doses as factors, the codone administered alone (5.2% vs. 2.6%) [31]. However, improvement was observed with a decreasing oxy- OXN less frequently induced nausea (6.3% vs. 10.5%), vom- codone/naloxone ratio and appeared to plateau at the 2:1 iting (1.3% vs. 4.3%), abdominal pain (1.3%, vs. 4.3%) and ratio, with the overall effect at 2:1 approximately 50% dyspepsia (0.6% vs. 2.5%) in comparison to PR oxycodone greater than at 4:1. No loss of analgesic efficacy with administered alone [32]. These differences might be ex- naloxone was observed. Addition of up to 40 mg of oral PR plained by naloxone antagonist effect on gastric and gut naloxone significantly reduced OIBD in patients with severe opioid receptors [33] and in consequence naloxone proki- chronic pain who were established on PR oxycodone. netic properties [34]. In a controlled study all AE and GI Naloxone at doses of 20 and 40 mg improved bowel function symptoms were more frequent in patients treated with OXN in comparison to the placebo (p < 0.05). The combination (37.7% and 23.8%, respectively) compared with PR oxy- was well tolerated with no unexpected AE. A trend towards codone (29.6% and 16.3%, respectively): abdominal pain an increase in diarrhea with the higher naloxone doses was (7.7%, 1.5%), constipation (0.8%, 1.5%) diarrhea (4.6%, observed. The 2:1 oxycodone/naloxone ratio was identified 3.0%), nausea (10.0%, 6.7%), vomiting (3.1%, 0.7%), re- as the most suitable. spectively [35]. Nadstawek et al. [21] evaluated patient assessment of the Long–term treatment with OXN over a period of up to 52 efficacy and tolerability of oral PR oxycodone when co– weeks of patients with chronic pain who have completed 12 administered with oral PR naloxone. A total of 202 patients weeks two phase III studies [31, 32] was safe [36]. Overall, with non–cancer and cancer pain who were on a stable PR the incidence of AE was 68%. There were 13% of serious oxycodone dose (40, 60 or 80 mg per day) were randomized AE. A total of 6.3% of treated patients discontinued therapy into groups that received 10, 20, 40 mg of PR naloxone or with OXN due to AE. The most commonly reported AE placebo. After 4 weeks of the maintenance phase, patients were constipation (9.2%), nausea (7.7%), back pain and de- were switched to PR oxycodone for 2 weeks. Efficacy was pression (6.3% each), and diarrhea (3.2%). Similar incidence good or very good in 50%, 67.4% and 72.5% of patients in of all AE of OXN (61.0%) and PR oxycodone (57.3%), GI the 10, 20 and 40 mg PR naloxone group, respectively, com- AE (20.9% and 21.7%; diarrhea 5.1% and 3.7%, respec- pared to 43.5% of patients in the placebo group. Patient as- 130 Current Drug Targets, 2014, Vol. 15, No. 1 Wojciech Leppert sessment of tolerability was ranked as good or very good by 0.0001) after one week, an increase in CSBM per one week 83.3%, 79.1% and 82.5% of patients in the 10, 20 and 40 mg (median 3.0 vs. 1.0) after 4 weeks of the treatment and lower per day PR naloxone dose group, respectively, compared intake during the study period in OXN group com- with 71.7% of patients in the placebo group. The mainte- paring to PR oxycodone group. Pain intensity scores were nance phase was preferred by patients in the PR naloxone comparable between the groups and consistent for the dura- groups. Efficacy of a 2:1 dose ratio of oxycodone to tion of the study. No unexpected AE attributable to OXN naloxone was evaluated as good or very good by 70.4% of were observed. The treatment with OXN was superior to PR patients compared with 43.5% treated with placebo. Toler- oxycodone administered alone in terms of bowel function, ability of the 2:1 dose ratio was ranked as good or very good while providing equivalent analgesia. by 81.5% of patients compared with 71.1% for the placebo Sandner–Kiesling et al. [36] conducted a long–term group and patients preferred the maintenance phase. analysis over a period of up to 52 weeks of OXN therapy of Vondrackova et al. [31] in a randomized, double–blind, the patients with chronic pain who have completed 12 weeks placebo– and active–controlled, parallel–group study dem- period in two phase III studies [31, 32]. The initial Brief Pain onstrated the superiority of an OXN combination over pla- Inventory – Short Form (BPI–SF) scores (3.9 ±1.52) of the cebo with respect to analgesic efficacy in patients with mod- average pain over the last 24 h remained low after 6 months erate to severe chronic low back pain. The full analysis (3.7 ± 1.59) and 12 months (3.8 ± 1.72) of the treatment. The population consisted of 463 patients. The times to recurrent BPI–SF mean scores of pain interference with activity and pain events were significantly longer in the OXN group with sleep remained low throughout the study period. The compared with placebo (p < 0.0001–0.0003). OXN reduced mean BFI score decreased from the initial 35.6 ± 27.74 to the risk of pain events by 42% (p < 0.0001). The appearance 20.6 ± 24.01 after 12 months of the treatment. The treatment of pain events was comparable for OXN vs. oxycodone was well tolerated with typical opioid AE. This study dem- alone, which confirmed that the addition of PR naloxone to onstrated that the treatment with OXN in daily doses of up to PR oxycodone had not negatively influenced oxycodone 80 mg/40 mg was safe and effective. analgesic efficacy. OXN provides patients with effective analgesia and improves OIBD. Moreover, the safety profile Löwenstein et al. [37] conducted prospective pooled data of OXN is comparable to other opioids with the exception of analysis of two controlled studies [32, 35] to demonstrate OIC, which indicates that the addition of PR naloxone im- non–inferiority in analgesic efficacy and the impact on proves tolerability. OIBD of OXN vs. PR oxycodone alone (20–120 mg/day) in patients with moderate–to–severe non–malignant pain and Simpson et al. [32] conducted a double–blind, multicen- OIC for 12 weeks. No statistically significant differences in ter trial in 322 adult patients with moderate–to–severe, non– analgesic efficacy were observed for the two treatments (p = cancer pain who required opioids in a dose range of 20–50 0.3197; non–inferiority p < 0.0001; 95% CI -0.07, 0.23) and mg per day of oxycodone. Patients were randomized to re- no statistically significant difference in frequency of analge- ceive OXN or PR oxycodone for 12 weeks. The primary sic rescue medication use. Improvements in BFI score were outcome was an improvement in constipation (BFI). The observed for OXN by week 1 and at every subsequent time secondary assessments focused on pain intensity and addi- point (-15.1; p < 0.0001; 95% CI -17.3, -13.0). AE incidence tional bowel parameters. A significant improvement in BFI was similar for both groups (61.0% and 57.3% of patients scores occurred with OXN compared with PR oxycodone with OXN and PR oxycodone alone, respectively). OXN after 4 weeks of the double–blind treatment (–26.9 vs. –9.4, provided effective analgesia and improved bowel function respectively; p < 0.0001), which had been observed after without compromising analgesic efficacy. only one week of the treatment and continued until study Cloutier et al. [40] assessed analgesic efficacy and safety end. A significant increase in the number of complete spon- of OXN compared to placebo in patients with chronic low taneous bowel movements (CSBM) and decrease in laxative back pain. Patients with moderate–to–severe pain who use were also observed. The oxycodone analgesic efficacy required opioid therapy entered 2–7 days washout period (for was not compromised as pain intensity remained stable opioids and laxatives) before randomization to receive either throughout the study period. The incidence of AE was com- OXN at a dose of 10mg/5 mg every 12 h titrated weekly parable in both groups and typical for opioid analgesics. The according to efficacy and tolerability to 20 mg/10 mg, 30 fixed–ratio combination of OXN is superior to PR oxy- mg/15 mg or 40 mg/20 mg every 12 h or placebo. After 28 codone alone and offers effective analgesia with significant days of the treatment patients were washed–out again and improvement of OIC. crossed–over to alternative treatment. The rescue medication Löwenstein et al. [35] in a randomized, double–blind, was a combination of acetaminophen/codeine 300 mg/30 mg double dummy, parallel–group, and multicentre study as- tablets given up to two tablets every 4 to 6 h as needed. Of sessed the use of higher OXN doses (converted from PR the 83 patients randomized 54 (65%) completed the study. oxycodone 60–80 mg per day and allowed titrate the dose up OXN provided better analgesia than placebo as measured by to 120 mg/day) in patients with moderate–to–severe non– VAS (48.6 ± 23.1 mm and 55.9 ± 25.4 mm; p = 0.0296) and malignant pain and OIC. During the pre–randomization pe- five–point pain intensity scale (2.1 ± 0.8 and 2.4 ± 0.9; p = riod, a total of 265 patients receiving opioids for moderate– 0.0415). A lower use of rescue analgesics was found in OXN to–severe non–malignant pain were converted to PR oxy- group (p = 0.0003). Both patients and investigators preferred codone and titrated to an effective analgesic dose. Subse- OXN after the double–blind phase and 79% of patients chose quently, patients were randomized to be treated either with to continue treatment with OXN during 6 months open–label OXN or PR oxycodone alone. What resulted was a signifi- phase. No difference was found with respect to AE including cant improvement in bowel function assessed by BFI (p < bowel function that was normal at baseline and during the Oxycodone/Naloxone in Pain Management and OIBD Current Drug Targets, 2014, Vol. 15, No. 1 131 study in both arms as demonstrated by low and comparable the treatment, and impact on constipation, and compared it to BFI scores. The only exception was somnolence that was PR oxycodone in patients with moderate–to–severe cancer more intense in OXN group compared to placebo (p = pain. A total of 185 patients were randomized to receive up 0.0045). No difference was found with respect to withdrawal to 120 mg/60 mg per day of OXN or 120 mg PR oxycodone symptoms which did not appear in any of the patient group over 4 weeks. After 4 weeks, mean BFI and PAC–SYM as demonstrated by low scores of the modified Subjective scores were significantly lower, with OXN and the mean Opioid Withdrawal Symptoms scale (SOWS). OXN was total laxative intake was 20% lower in this patient group than effective for the management of chronic low back pain of in the case of PR oxycodone. The mean BPI–SF scores were moderate–to–severe intensity. similar for both treatments and the consumption of rescue Hermanns et al. [41] in a large, observational study ad- analgesics was low and comparable between the two patient ministered OXN (in the daily dose range of 20 mg/10 mg to groups. QoL (assessed by the EORTC QLQ–C30 and the 40 mg/20 mg) over a period of up to 4 weeks to 1488 pa- EuroQoL) results showed better scores with respect to con- tients with severe neuropathic non–malignant pain. During stipation–related symptoms in the group treated with OXN. the treatment with OXN, the mean pain intensity decreased AE were similar in both patient groups. Specifically, no dif- in both opioid–naive and opioid–pretreated patients. After 4 ference in scores of the modified SOWS was found between weeks of the treatment, the BFI scores dropped from the the two patient groups. The results suggest that OXN in initial 41.6 ± 31.6 to 16.5 ± 19.6 (p < 0.001), reflecting nor- doses of up to 120 mg/60 mg per day may provide effective mal bowel function. Additionally, QoL was improved by analgesia and improve bowel function. 47%. OXN provided effective analgesia, improved bowel Clemens et al. [45] conducted an open, uncontrolled function measured by BFI and QoL over the period of 4 study among 26 patients with advanced cancer who received weeks of the treatment. different opioids due to severe pain. The former opioid treat- Gatti et al. [42] in a retrospective, single center, ment was switched to OXN at a maximum daily dose of 40 observational study assessed the effectiveness and safety of mg/20 mg that was administered for the period of 14 days. OXN in consecutive patients with constipation and chronic Bowel function was assessed by BFI, the Bristol Stool Form non–malignant pain, both in opioid–naive and opioid– Scale (BSFS) and the Patient Global Impression of Change tolerant patients. Efficacy was assessed by pain intensity, Scale (PGIC). In 21 patients, constipation improved, as bowel function, effective OXN dose, the Patients’ Global measured by BFI, BSFS and PGIC, while providing ade- Impression of Change (PGIC) scale, rescue paracetamol, and quate analgesia. The most frequent AE were nausea (in 9 laxative use. Of 1,051 patients starting on the OXN patients) and abdominal pain (in 5 patients). Two patients combination, 1,012 completed 2 months of treatment. experienced diarrhea. Opioid withdrawal symptoms were not Overall, OXN was associated with a significant decrease in observed. In 5 patients it was necessary to switch to hydro- pain intensity (p < 0.001), a reduced need for rescue morphone due to inadequate pain relief. paracetamol (p < 0.001), and a PGIC score of “very much Schutter et al. [46] assessed OXN efficacy and safety in a improved” or “much improved” in 84.0% of the patients. daily clinical practice. A total of 7836 patients from 6496 Constipation markedly decreased (p < 0.001) despite a centres were included and followed for 4 weeks. The major- reduced laxative use (p < 0.001 vs. baseline). The most ity of them were opioid–pre–treated (n = 5849, 74.6%), frequent AE were somnolence (2.0%), dizziness (1.1%), and while 1963 (25.1%) were opioid–naive. Previous analgesics confusion (1.0%). Clinical differences in endpoints were were prescribed in 95.5% of patients: non–opioids in 19.8%, observed between opioid–naive and opioid–tolerant patients, weak opioids in 33.9% and strong opioids in 36.0% of pa- and among age stratified groups, but efficacy was similar to tients. Pain was evoked by musculo–skeletal disorders that of the overall population. OXN was effective and well (85.9%), including degenerative disease of the spine tolerated in moderate–to–severe chronic pain in patients with (64.7%), /arthritis (34.2%), osteoporosis constipation, providing analgesia and relief from bowel (20.2%), nervous system disorders (20.8%), malignant dis- dysfunction. Consistent efficacy across patient subgroups ease (17.3%) with multiple causes possible. The mean ob- provides guidance for daily management of chronic pain servation period was 33.6 ± 13.2 days. A total of 68.3% pa- when therapy options are limited due to bowel dysfunction tients started the treatment with OXN at a dose of 10 mg/5 regardless of age or previous medication. mg twice a day (daily doses range 10 mg/5 mg – 60 mg/30 Dunlop et al. [43] assessed cost–effectiveness and QoL mg). The percentage of patients treated with doses higher and compared OXN with PR oxycodone in patients with than 10 mg/5 mg increased during the observation period. moderate–to–severe non–malignant pain and OIC. Although Analgesia (BPI–SF) improved; the strongest pain fell the OXN direct treatment cost was slightly higher than that from 6.8 ± 1.8 at baseline to 3.9 ± 2.1 at the final visit by 2.9 of PR oxycodone, when analyzing constipation treatment points (95% CI: 2.8, 3.0; p < 0.001) with similar results ob- costs and benefits of OXN in terms of improved quality– tained for the least pain intensity, pain on average and pain adjusted life–year, OXN was the cost–effective option in the right now (p < 0.001 for all differences). Bowel function UK. However, the model used is this study is limited by 12– improved in the course of the treatment. The mean global week period of the data analysed from a randomised, con- BFI decreased from 38.2 ± 30.7 to 15.1 ± 18.5 for both trolled trial [32] and primary care physician opinion. opioid–naive and opioid–pretreated patients with more pro- nounced difference in the latter group. The ease of defeca- Patients with Cancer Pain tion, the sensation of incomplete evacuation and patients’ Ahmedzai et al. [44] in a randomized, double–blind, mul- personal assessment of constipation improved (p < 0.001 for ticentre study, assessed OXN analgesic efficacy, tolerance of all differences). Other symptoms – frequency and severity – 132 Current Drug Targets, 2014, Vol. 15, No. 1 Wojciech Leppert improved comparing the first and the third visit: nausea Patients with Postoperative Pain 43.4% and 19.6%, constipation 63.1% and 31.1%, abdominal Kuusniemi et al. [47] conducted three studies in patients pain 39.5% and 13.9%, diarrhea 6.1% and 4.7%, dizziness with postoperative pain. The first was a controlled (random- 41.7% and 23.2%, respectively. Vomiting, appetite and ab- ized, double–blind, double–dummy, parallel) study of pa- dominal cramps also improved in frequency and severity. Laxatives were taken by 28.2% (5.5% of opioid–naive and tients with postoperative pain after knee arthroplasty. A total of 137 patients were randomized to be treated either with 35.9% of opioid–pretreated patients) of patients at the first OXN or PR oxycodone. Both analgesics rendered similar and by 12.4% (3% and 18%, respectively) of patients at the analgesia as measured by NRS at rest and on movement and final visit. QoL was assessed by the impact of pain on gen- similar AE (the most frequent being constipation, nausea, eral activity, mood, ability to walk, normal walk, relationship vomiting and insomnia). In the second study, OXN (n = 43) with others, sleep, enjoyment of life. Pain interference de- creased in all items with a total improvement of QoL by was compared with other opioids (n = 37) during rehabilita- tion after knee arthroplasty in a non–interventional open– 43%. label prospective study. Patients indicated enhanced efficacy A total of 3881 AE were recorded in 1556 (20.0%) of pa- and tolerability for OXN compared with other opioids and tients. In 50.5% the severity was mild, in 29.3% moderate used less laxatives when treated with OXN than with other and in 20.2% severe. The most frequent AE were nausea and opioids. In the third study patients after cervical spine sur- constipation (3.8% each) and dizziness (2.8%). A total of gery (n = 24) and undergoing rehabilitation following ortho- 244 serious AE were documented in 177 patients (2.3%). In pedic joint surgery were switched from other opioids to the majority of patients with serious AE there was no causal OXN treatment (n = 20) with the single dose range of 5/2.5 relationship to the use of OXN in the opinion of the treating mg – 20/10 mg during quality improvement program. As a physicians and the sponsor. Treatment with OXN was dis- result of the switch, a significant improvement in bowel continued in 1157 patients (14.8%), with 363 patients dis- function and passing urine was noted during treatment with continuing due to AE (31.4% of all treatment discontinua- OXN. In both studies no safety concerns were found and no tions, 4.6% of all patients) followed by insufficient analgesia serious AE were observed. (312 patients, 27.0% and 4.0%, respectively). A total of In a recent study, Comelon et al. [48] compared OXN 17.1% of all patients who dropped out discontinued because with PR oxycodone in female patients with pain after non– the indication (moderate–to–severe pain) was no longer malignant, elective, laparoscopic supra–cervical or total given. In the final assessment, 88.4% and 84.2% of the phy- sicians and patients assessed the OXN efficacy as good or laparoscopic hysterectomy in a randomized, double–blind, parallel and prospective trial. The first dose of study medica- very good; 89.8% and 87.1%, respectively, assessed toler- tions (either OXN 10/5 mg or PR oxycodone 10 mg) along ability as good or very good. Physicians concluded that, in with paracetamol and diclofenac were administered orally 1– comparison with the previous treatment, tolerability of the 2 h prior to the surgery. The single doses of the study drugs combine treatment was better or much better in 85.45% of were repeated every 12 h for a total of 3 days. Oxycodone patients. Patient acceptance of the medication evaluated by physicians was good or very good in 88.5% of patients. administered intravenously via a PCA (patient–controlled analgesia) pump or oral IR oxycodone 5 mg when PCA In a case report, Mercadante [38] depicted a cancer pa- pump was discontinued were given as rescue analgesics. tient with severe pain who required high OXN daily doses Patients were followed for the first 7 days after surgery with (240 mg/120 mg) which were ineffective. A switch to PR pain (NRS) and bowel function (BFI and BSFS) assess- oxycodone alone at a daily dose of 240 mg provided satisfac- ments. tory analgesia. It may suggest that at higher doses (240 A total of 109 patients were randomized and received ei- mg/120 mg per day) OXN provides inferior analgesia in ther OXN (48 patients) or PR oxycodone (49 patients), with comparison to PR oxycodone administered alone at a dose of 40 and 45 patients completing the treatment, respectively. 240 mg daily. Both groups were similar with respect to pain and bowel Kang et al. [39] reported a 50–year–old woman diag- function scores and the use of oxycodone for breakthrough nosed with gastric cancer with peritoneal seeding and exten- pain episodes. Furthermore, both patient groups did not dif- sive thrombosis in the portal vein and abdominal pain (NRS fer with respect to AE; no cases of strong sedation or respira- 6). PR oxycodone at a dose of 10 mg administered twice tory depression were found in any patient group. daily provided satisfactory analgesia (NRS 2). However, due to OIC not amenable to laxative therapy, the patient was THE PLACE OF OXYCODONE/NALOXONE IN THE rotated to OXN at a dose of 10 mg/5 mg twice daily. After MANAGEMENT OF PATIENTS WITH PAIN AND taking OXN the patient experienced severe pain (NRS 7) and OPIOID–INDUCED BOWEL DYSFUNCTION several symptoms (chills, diarrhea, general weakness, and OXN provides similar analgesic efficacy to oxycodone, sweating) suggesting withdrawal. The patient returned to the with improvement in bowel function expressed by better former treatment with PR oxycodone 10 mg administered results of BFI, PAC–SYM, PAC–QOL, more frequent twice daily and her pain was again well relieved (NRS 3) and CSBM and lower consumption of laxatives. OXN renders other symptoms disappeared. This case suggests develop- similar analgesia and reverses OIC in comparison to oxy- ment of a collateral circulation due to portal vein thrombosis codone administered alone in patients with chronic non– and naloxone directly reaching CNS and evoking withdrawal malignant pain [37], also with neuropathic component [41], symptoms. in cancer patients with pain [44, 45] and in patients with postoperative pain [47, 48]. The latter are inconclusive with Oxycodone/Naloxone in Pain Management and OIBD Current Drug Targets, 2014, Vol. 15, No. 1 133 respect to bowel function most probably due to the short in acute abdominal conditions and in the case of allergy to period of the treatment, low doses of OXN used and other the drug. In a few patients with GI diseases, MNTX caused factors that may disturb normal bowel function in the post- GI perforation. Furthermore, clinical studies have demon- operative period. Interestingly, OXN improved also passing strated efficacy of MNTX in patients with advanced diseases urine in patients with postoperative pain [47]. OXN reduces and OIC [55-58]. However, long–term efficacy and safety of OIBD and improves patients’ compliance and QoL. Cur- MNTX has not been clearly established [59]. rently, OXN is registered in daily doses up to 80 mg/40 mg. (NKTR–118) is a polymer conjugate of the However, controlled studies conducted in patients with non– opioid antagonist naloxone administered once daily by the malignant [35] and cancer–related pain [44] demonstrated oral route. The moiety limits naloxegol that the daily dose of 120 mg/60 mg may be safe and effec- capacity to cross the blood–brain barrier [60]. In phase 2, tive. Studies with higher daily doses of OXN are ongoing. randomized, double–blind, placebo–controlled, dose– OXN may be administered to opioid–naive patients with escalation study, the efficacy and safety of three dose levels moderate–to–severe pain as well as to patients with pain not of oral naloxegol in the treatment of OIC in patients with responding to weak opioids. It may also be effective in pa- non–malignant or cancer–related pain was evaluated. The tients rotated from other step 3 opioids which cause severe dose of 25 mg naloxegol was chosen to be further explored OIBD not responding to traditional laxatives. OXN may de- in phase 3 studies [61]. crease symptoms of OIBD through naloxone blocking opioid is used in inpatients to restore bowel function receptors occupation by oxycodone. The unique and specific after surgery for no more than 7 days (15 doses) and cannot mechanism of control of OIBD has the potential advantage be prescribed for outpatients. However, it is contraindicated of the treatment of OIBD symptoms that significantly de- for the treatment of OIBD in patients with advanced diseases crease patients’ QoL. This especially applies to high–risk due to the risk of cardiac infarction [62-65]. populations, such as patients with advanced cancer, those with GI tumors or patients who require concurrent treatment CONCLUSIONS with opioids and other agents that impair bowel function [49]. OIBD is a common complication in patients receiving long–term treatment with opioids. A significant progress has The European Society for Clinical Oncology [50] and been made with targeted therapies for the management of UK experts in myeloma [51] suggest the use of OXN for pain management in cancer and myeloma patients, respec- patients with symptoms of OIBD, namely OXN and MNTX. Controlled clinical studies are needed to demonstrate long– tively [52]. OXN may not only be used for the management term efficacy, safety and cost–effectiveness of these new of patients with chronic pain who developed OIBD, but also therapies. New approaches may decrease the need for un- more effectively, in the prevention of OIBD development pleasant and poorly accepted rectal interventions, reduce [40]. The evidence from OXN studies conducted in patients OIBD management costs and improve patients’ compliance with chronic non–malignant and cancer–related pain points the role of OXN in prevention and treatment of OIBD in to opioid therapy. As a result of the more effective targeted OIBD treatment, the effectiveness of pain management may patients who require opioid therapy for moderate–to–severe be increased, having a positive influence on patients’ QoL. pain. 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Received: February 21, 2013 Revised: August 22, 2013 Accepted: August 27, 2013

PMID: 24020972