Journal of Pain & Palliative Care Pharmacotherapy. 2014;Early Online:1–10.Copyright © 2014 Informa Healthcare USA, Inc.ISSN: 1536-0288 print / 1536-0539 onlineDOI: 10.3109/15360288.2014.938881

CASE REPORT

Case Report: Efficacy and Tolerability of Ketaminein Opioid-Refractory Cancer Pain

Priya Amin, Eric Roeland, and Rabia Atayee

ABSTRACT

A 36-year-old female with metastatic breast cancer involving bones, liver, lung, and pleura/chest wall with wors-ening back pain received weight-based intravenous (IV) ketamine and was transitioned to oral ketamine forcancer-related neuropathic pain. She had responded poorly to outpatient pain regimen of oxycodone sustainedand immediate release, hydromorphone, gabapentin, and duloxetine (approximate 480 mg total oral morphineequivalents [OME]), reporting an initial pain score of 10/10. She was started on hydromorphone parenteralpatient-controlled analgesia (PCA) bolus dose in addition to her outpatient regimen. Despite escalating doses ofopioids and the addition of a lidocaine 5% patch, the patient’s pain remained uncontrolled 6 days after admission.On hospital day 7, utilizing a hospital weight-based ketamine protocol, the patient was started on subanestheticdoses of ketamine at 0.2 mg/kg/h (288 mg/24 h) and titrated over 2 days to 0.4 mg/kg/h (576 mg/24 h). Then,a 3-day rotation from intravenous to oral ketamine was initiated, and the patient was discharged on ketamineoral solution, 75 mg every 8 hours. When the patient’s dose was increased to 0.4 mg/kg/h, adequate pain reliefwas charted by the nurse within 120 minutes, “patient pain free and resting comfortably.” Her pain continued tobe well managed, with an average pain score of 5/10 with the ketamine continuous infusion and sustained withconversion to oral ketamine without any report of side effects. This was a 37% reduction in pain scores. Withthe patient’s stabilized dose of ketamine, opioid requirements decreased by 61.4% (1017.5 mg reduction in totalOME). The use of weight-based dosing of IV continuous infusion and transition to oral ketamine was effectiveand tolerable in the management of opioid-refractory, neuropathic cancer pain. It is hoped that this case reportpromotes a discussion regarding ketamine dosing in refractory neuropathic cancer pain.

KEYWORDS cancer, ketamine, NMDA antagonist, pain, refractory

INTRODUCTION

This report presents a case in which continuous in-travenous and orally prepared ketamine was effective

Priya Amin, PharmD, is with the University of California San DiegoSkaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, Califor-nia, USA. Eric Roeland, MD, is Assistant Clinical Professor of Gastroin-testinal Oncology and Director of Clinical Research in Symptom Man-agement at the University of California San Diego Moores Cancer CenterDoris A. Howell Palliative Medicine Service, La Jolla, California, USA. Ra-bia Atayee, PharmD, BCPS, is an Associate Clinical Professor at the Uni-versity of California San Diego Skaggs School of Pharmacy and Pharma-ceutical Sciences, and is with University of California San Diego MooresCancer Center Doris A. Howell Palliative Medicine Service.

The authors thank Dr. William Mitchell for his expert advice and guid-ance on the manuscript.

Address correspondence to: Rabia S. Atayee, PharmD, BCPS, School of Phar-macy 9500 Gilman Drive, MC 0675 La Jolla, CA 92093-0675, USA (E-mail:ratayee@ucsd.edu).

and tolerable at doses and routes different than thosereported in the recent phase III trial published byHardy and colleagues.1

In 2012, a 36-year-old female with metastaticbreast cancer status post left mastectomy involvingbones, liver, lung, pleura, and chest wall was admit-ted to University of California San Diego MedicalCenter with dyspnea due to her thoracic diseaseprogression and uncontrolled pain. The patienthad experienced 4 months of progressive back painradiating to her right of the spine and chest. Shehad no prior history of alcohol or drug dependency.On presentation, her pain score was 10/10 while shewas on an outpatient regimen of sustained-releaseoxycodone (OxyContin) 80 mg by mouth twice daily,immediate-release oxycodone 30 mg every 6 hours asneeded, oral hydromorphone 2 mg every 4 hours asneeded (approximately 480 mg total oral morphine

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2 JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY

TABLE 1. Patient Opioid Use

Average pain score% Change OME (percent reduction

Time point Opioids OME (from day 0) from day 0)

Prior to admission Oxycodone SR 80 mg twice dailyOxycodone IR 30 mg every 6 hours as neededOral hydromorphone 2 mg every 4 hours as needed

480 mg N/A 10/10 (NA)

Day 0 ketamine IV Oxycodone SR 320 mg every 12 hoursIV hydromorphone 1.5 mg bolus every 15 minutes

(total 46.5 mg)Initiated ketamine IV continuous infusion

0.2 mg/kg/h

1657.5 mg N/A 8/10 [7–9/10] (NA)

Day 1 ketamine IV Oxycodone SR 320 mg every 12 hoursIV hydromorphone 1.5 mg bolus every 15 minutes

(total 27 mg)Increased ketamine IV continuous infusion

0.3 mg/kg/h

1365 mg −17.6% 7/10 [6–8/10] (12.5%)

Day 2 ketamine IV Oxycodone SR 320 mg every 12 hoursIV hydromorphone 1.5 mg bolus every 15 minutes

(total 24 mg)Increased ketamine IV continuous infusion

0.4 mg/kg/h

1320 mg −20.4% 6/10 (25%)

Day 3 ketamine IV Oxycodone SR 160 mg every 12 hoursIV hydromorphone 1.5 mg bolus every 15 minutes

(total 18 mg)Continued ketamine IV continuous infusion

0.4 mg/kg/h

750 mg −54.8% 6/10 (25%)

Post 3 day conversionto oral ketamine

Oxycodone SR 160 mg every 12 hoursOral hydromorphone 8 mg as needed (total 32 mg)

640 mg −61.4% 5/10 [4–6/10] (37.5%)

Note. IR = immediate release; IV = intravenous; OME: oral morphine equivalent in 24 hours; SR = sustained release.

equivalents [OME]2; Table 1), gabapentin 300 mgevery 8 hours, and duloxetine 30 mg daily.

Upon examination, the patient was alert and con-versational. She had an area of fullness on her rightback with no edema. A computed tomography (CT)scan of her chest demonstrated extensive, progressivedisease in her right lung, pericardium, pleura, chestwall, and bones. A CT scan of her abdomen andpelvis showed progressive liver, gluteal, and boneymetastases. Initially, the patient was started on alloutpatient pain medications with an additional orderof hydromorphone 2 mg intravenous (IV) or 4 mgoral as needed. Within the first 24 hours, the patientreceived 20 mg of IV hydromorphone (approximate720 mg total OME) with inadequate pain reliefand a pain score of 9–10/10. She reported chestpain “across breast” and described it as “sharp”pain that “comes and goes” radiating across herback. She was then started on a hydromorphoneintravenous patient-controlled analgesia (PCA) with0.2 to 0.5 mg demand doses only in addition to herother pain medications.

The University of California San Diego Doris A.Howell Palliative Care Service was consulted on hos-

pital day 5 to manage the patient’s complex mixtureof nociceptive and neuropathic pain. The multidisci-plinary palliative care team recommended discontin-uation of oxycodone controlled release (CR) and wasreplaced with basal hydromorphone PCA at 1.5 mgper hour, which was titrated up to 2 mg per hourwith 1 mg bolus every 10 to 15 minutes demanddose. The patient used the demand dose 18 timesin the preceding 24 hours, but achieved pain controlwith slight somnolence (approximately 990 mg totalOME). The patient reported severe pain despite sub-sequent increases in PCA demand dose to 1.5 mg ev-ery 15 minutes. The patient’s basal PCA pump in-fusion was discontinued, and she was restarted at ahigher dose of oxycodone 320 mg CR every 12 hoursin addition to lidocaine 5% patch. On hospital day6, she continued to have escalating opioid needs, asevidenced by her hydromorphone PCA 1.5 mg de-mand dose use of 31 times in the proceeding 24-hourtime period, with pain score in the 7–9/10 range (ap-proximate 1657.5 mg total OME). We determinedthat high-dose sustained-release oxycodone and hy-dromorphone PCA would not be a successful strategyfor pain management in this patient.

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Case Report 3

NEUROPATHIC PAIN

Neuropathic pain arises as a direct consequence of alesion or disease affecting the somatosensory system.3

Neuropathic pain can result from damage to theperipheral nervous system (e.g., diabetic peripheralneuropathy, postherpetic neuralgia) or from centralnervous system (CNS) damage (e.g., spinal cord in-jury, multiple sclerosis, stroke, brain metastases).4

Patients can experience both peripheral and centralneuropathic pain simultaneously.5 This can be fur-ther complicated by central and peripheral sensitiza-tion characterized as increased responsiveness and re-duced threshold of nociceptive neurons in the CNSand periphery to their normal input. Spontaneousdischarges and increases in receptive field size mayalso occur in this phenomenon.6

First-line treatments of neuropathic pain includegabapentin and pregabalin, tricyclic antidepressants,serotonin-norepinephrine reuptake inhibitors, andtopical lidocaine.7,8 When patients do not haveadequate response to these therapies, second-linetreatments can be used alone or in combinationwith first-line treatments. Second-line treatmentsinclude opioids (oxycodone, morphine, methadone)and nonopioids. Last-line or refractory treatmentsthat have limited data available to support safety andefficacy include cannabinoids, botulinum toxin A,capsaicin, and ketamine.7,8

KETAMINE

Ketamine is a phencyclidine analog referred toas a “dissociative anesthetic.”9,10 It is analgesic atsubanesthetic doses.10 Ketamine is a schedule IIIcontrolled-substance medication, and its approvedindications include diagnostic and surgical proce-dures that do not require skeletal muscle relaxation,induction of anesthesia prior to administrationof other general anesthetics, and to supplementlow-potency agents such as nitrous oxide.11 Off-labelindications include asthma/bronchoconstriction,10

treatment of addiction12, depression,13 prolongedepileptic seizures, and pain (e.g., neuropathic,nociceptive, postoperative, complex regional painsyndrome).14

Ketamine’s primary mechanism of action is po-tent N-methyl-D-aspartate (NMDA) receptor an-tagonism. It also works on muscarinic/nicotiniccholinergic receptors, serotonin, norepinephrine, anddopamine (5-HT/NE/DA) receptors, L-type calciumand sodium channels, and opioid receptors.10 Thepharmacokinetics of ketamine is important to note,especially when administering this medication. The

IV formulation has an onset in seconds and usu-ally last about 30 seconds to 5 minutes, whereasthe oral formulation has an onset of 15 to 20 min-utes with duration of 1 to 2 hours.10 The IV routehas 90% bioavailability compared with 16% bioavail-ability with oral route.15 Oral ketamine undergoesfirst-pass metabolism and is metabolized to norke-tamine, which has an equipotent analgesic effect toketamine.16,17 Oral norketamine levels, however, areabout 2 to 3 times higher than IV levels. Therefore,dose conversion from the intravenous to the oral routeis 3:1.18 The half-life of ketamine is about 2 to 3 hoursand 4 hours for norketamine.19

Dosing of IV ketamine in the literature ranges from0.1 mg per kg per hour up to 0.8 mg per kg perhour.20–22 Daily doses up to 4800 mg in 24 hourshave also been reported.23–25 Oral ketamine dosesrange from 10 to 200 mg every 6 to 8 hours.15,19 Aloading dose for IV infusion is typically avoided due tothe potential of increased CNS side effects, includingdissociative anesthesia, euphoria/dysphoria, halluci-nations, and agitation. Hallucinations are more com-mon in females, with higher doses, and with rapid IVboluses. Hallucinations can be prevented by pretreat-ing with benzodiazepines or haloperidol. This effectis seen less with norketamine.15 Ketamine has a widetherapeutic range, making overdose difficult. Patientswho have overdosed have recovered uneventfully afterreceiving 10 times the normal dose.10

KETAMINE IN THE LITERATURE FORPAIN MANAGEMENT

There are over 50 published clinical trials on theuse of ketamine in pain (e.g., neuropathic, postop-erative, opioid-tolerant/refractory, acute, mucositis).The majority of these are case reports with small sam-ple sizes, except for one phase III trial by Hardy andcolleagues.1 Table 2 summarizes the existing litera-ture on ketamine for cancer-related pain.21–23,25–34

A recent randomized, double-blind, placebo-controlled trial by Hardy et al.1 analyzed the efficacyand toxicity of subcutaneous ketamine in the man-agement of cancer pain in 185 patients. Either ke-tamine or placebo was given in a 5-day schedule start-ing at the first dose level of 100 mg per 24 hours.Doses could be increased to 300 mg or a maximumof 500 mg per 24 hours. Of note, ketamine dosingwas not weight-based. The primary outcome was de-fined as a reduction in pain score by 2 or more pointsfrom baseline in the absence of more than four break-through doses of analgesia over the previous 24 hours.Mean pain scores in this study improved over time forall participants with no difference between arms. This

C© 2014 Informa Healthcare USA, Inc.

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Case Report 7

trial failed to show any additional clinical benefit forketamine, while significantly increasing toxicity com-pared with placebo.

KETAMINE USE AT THE UNIVERSITYOF CALIFORNIA SAN DIEGO

The University of California San Diego Health Sys-tem currently has a protocol for ketamine IV infusionfor refractory pain. Ordering ketamine is restrictedto the pain anesthesiology or palliative care service.Typical dosing is 0.2 to 0.5 mg per kg per hour con-tinuous infusion with no bolus dose. Oral (PO) dosecan be calculated based on a 3:1 ratio of IV:PO. BothIV and oral ketamine are titrated daily by 30% over3 days until the patient is no longer on IV ketamineand on the full dose of oral ketamine. Maximum oralketamine dosing used is 200 mg every 6 hours. Forpatient accessibility, a local pharmacy is able to com-pound oral ketamine solution for patients at an af-fordable price ($70 for 100-mL bottle of 50 mg/mL).

METHODS

Given the patients’ opioid-refractory pain and opioid-induced sedation, the palliative care team recom-mended the use of subanesthetic dose of intravenous(IV) ketamine infusion in addition to the patient’spain regimen, including hydromorphone PCA de-mand dose at 1.5 mg every 15 minutes, sustained-release oxycodone at a dose of 320 mg twice daily, li-docaine 5% patch, gabapentin 300 mg every 8 hours,and duloxetine 30 mg daily.

Ketamine was initiated at 0.2 mg per kg per hour(288 mg per 24 hours) per University of Califor-nia San Diego Medical Center protocol, and the ke-tamine infusion was titrated up to 0.4 mg per kg perhour (576 mg per 24 hours) over 3 days (Table 1).Our patient’s weight was 60 kg. On day 0 of ketamineinfusion, the patient received ketamine at 0.2 mg perkg per hour (288 mg per 24 hours) and continued onall other pain medications. On day 1 of ketamine in-fusion, the dose of ketamine was increased to 0.3 mgper kg per hour (432 mg per 24 hours), with the samedoses of all other pain medications. However, the pa-tient only required 18 demand doses of hydromor-phone 1.5 mg PCA compared with 31 demand dosesthe day before. On day 2 of ketamine infusion, thepatient was increased to ketamine at 0.4 mg per kgper hour (576 mg per 24 hours), with a decrease insustained-release oxycodone from 320 mg twice dailyto 120 mg twice daily. The patient also required 16demand doses of hydromorphone 1.5 mg PCA com-

pared with 18 demand doses the day before. On day3 of ketamine infusion, the patient was continued onketamine at 0.4 mg per kg per hour (576 mg per24 hours); however, she only required 12 demanddoses of hydromorphone 1.5 mg PCA compared with16 demand doses the day before. At this point, the pa-tient was converted to oral medications, including ke-tamine oral solution 75 mg every 8 hours using a 3:1IV:PO conversion over 3 days (Figure 1) in prepa-ration for discharge home (see ketamine discussionabove).

RESULTS

Prior to the start of ketamine, the patient required1657.5 mg OME and still reported pain to be out ofcontrol. Using an 11-point pain intensity numericalrating scale and when asked to rate her pain from 0to 10 where 0 is defined as “no pain” and 10 is de-fined as “the worst possible pain,” the patient ratedher pain 7 to 9 (Table 1). After 24 hours of ketamineIV infusion, the patient required 18 hydromorphonePCA demand doses compared with 31 demand dosesfrom the previous 24 hours (1365 OME, 17.6% re-duction). With the addition of ketamine, the patientalso reported a lower pain score of 6 to 8 on a scaleof 0 to 10 and was more alert, conversational, andpleasant. The ketamine infusion was further titratedup to 0.3 mg per kg per hour (432 mg per 24 hours),and all other pain medications were continued. Byday 2 of the ketamine infusion, the patient only re-quired 16 hydromorphone PCA doses in a 24-hourperiod (1320 mg OME, 20.4% reduction). She re-ported a pain score of 6/10 and was alert, conversa-tional, smiling, and able to ambulate. Her sustained-release oxycodone dose was decreased in half from320 mg every 12 hours to 160 mg every 12 hours andketamine infusion was further titrated up to 0.4 mgper kg per hour (576 mg per 24 hours). By day 3 ofketamine infusion, the patient only required 12 hy-dromorphone PCA demand doses in a 24-hour pe-riod (750 mg OME, 54.8% reduction), with a painscored of 6/10, which she stated was her goal painscore and did not want any further dose titration. Thepatient continued to be alert and conversational forprolonged periods and denied any side effects.

As the patient’s pain stabilized and the internalmedicine primary team prepared for discharge, painpharmacotherapy was converted to an oral regimen(Table 3). Hydromorphone PCA demand doses wereconverted to oral hydromorphone. The IV PCA dosewas 1.5 mg and the patient was requiring about 12doses per day, which is calculated to 18 mg of IVhydromorphone per 24 hours. Using a ratio of 1:3

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8 JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY

FIGURE 1. Pain medication and pain score during IV ketamine infusion. (A) IV ketamine dosing (mg/kg/h). (B) 24-Houroral morphine equivalents (mg). (C) Average pain score (n/10).

going from IV hydromorphone to oral hydromor-phone, we calculated 54 mg of oral hydromorphoneper day. This further calculated to approximately5 mg every per 2 hours. The patient was first startedwith hydromorphone 4 mg orally every 2 hours asneeded for pain and then further titrated to eight mgorally every 2 hours as needed for pain for best re-sponse. A 3-day rotation from IV to oral ketamine wasinitiated with a goal dose of 75 mg every 8 hours of ke-tamine oral solution. By the end of the 3-day rotation,the patient required four doses of oral hydromor-phone 8 mg in 24 hours and was ambulating aroundthe unit. On a stable dose of oral ketamine, the patientreported a pain score of 4 to 6 out of 10, which paral-leled a 61.4% OME reduction to 640 mg. There wasan overall 37% reduction in pain score since the ini-tiation of the ketamine infusion. The patient was dis-charged on a regimen of sustained-release oxycodone160 mg every 12 hours, hydromorphone 8 mg oral ev-

TABLE 3. Ketamine IV to Oral 3-Day Rotation

Day Oral ketamine dose IV ketamine dose

1 25 mg every 8 hours 0.27 mg/kg/h2 50 mg every 8 hours 0.13 mg/kg/h3 75 mg every 8 hours 0

ery 2 hours as needed, ketamine oral solution 75 mgevery 8 hours, gabapentin 300 mg every 8 hours, lido-caine 5% patch every 24 hours, and duloxetine 30 mgdaily. Compounded ketamine oral solution (ketamineIV solution 50 mg per 5 mL, purified water, flavoringagent) was available for pick up at an outpatient phar-macy nearby. At a follow-up oncology visit a few dayspost discharge, the patient reported, “ketamine pro-vided the first pain relief she has had in over a year.”

DISCUSSION

Opioids and first-line neuropathic pain medicationsmay not always effectively treat mixed nociceptiveand neuropathic pain in the setting of progressivemetastatic cancer. As our patient’s chronic cancerpain escalated, it likely led to central and peripheralsensitization. This could explain the contrast betweenher poor response to escalating doses of opioid andexcellent response to ketamine. After the initiation ofketamine, the patient’s pain score decreased approx-imately from 8/10 (7–9/10) to 5/10 (4–6/10), with apain score reduction of 37%. In chronic pain trials,a reduction of approximately 30% on an 11-pointpain intensity numerical rating scale represented aclinically important difference.35 In addition to the

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Case Report 9

clinically significant reduction in pain, the patientshowed an increased ability to ambulate. From thepatient’s admission to discharge 9 days later, herOME decreased by 61.4% (from 1657.5 mg to640 mg daily).

When considering appropriate ketamine dosing,it is critical to note that the study by Hardy andcolleagues utilized fixed ketamine doses (100 mg,300 mg, and 500 mg in 24 hours) that were notweight-based. If we calculate weight-based dosing forthe average 70-kg patient, the continuous infusionrate would be 0.06 mg per kg per hour (100 mg per24 hours), 0.18 mg per kg per hour (300 mg per24 hours), and a maximum of 0.29 mg per kg perhour (500 mg per 24 hours). This patient weighed60 kg and ketamine was initiated at 0.2 mg per kgper hour (288 mg per 24 hours) and titrated up to0.4 mg per kg per hour (576 mg per 24 hours). Atthe highest dose, the patient reported adequate painrelief with no related side effects. In the ketamine lit-erature (see Table 2), doses up to 0.8 mg per kg perhour have been used in patients to achieve adequatepain control.20–22

Based on our clinical experience, we questionwhether the negative results in the Hardy study maybe due to the low dose of ketamine selected and lackof weight-based dosing. We hope this case reportpromotes a discussion regarding ketamine dosingin refractory neuropathic cancer pain. This patientexperienced a marked decrease in pain and requiredsignificantly less opioid pharmacotherapy with theinitiation and titration of IV ketamine. Cancer pa-tients who have received standard pharmacotherapyfor neuropathic pain management without successfulpain control may benefit from an observed trial ofadequately dosed ketamine infusion. In patients forwhom ketamine IV infusion is successful, transition-ing to equianalgesic oral ketamine solution may bea suitable option. We hope that future well-poweredcontrolled trials evaluate various doses, includingweight-based and higher doses of ketamine with useof all routes, including continuous infusion and oralketamine.

Declaration of interest: The authors report no con-flicts of interest. The authors alone are responsible forthe content and writing of the paper.

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RECEIVED: 17 February 2014REVISED: 7 April 2014

ACCEPTED: 21 April 2014

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