Spinal analgesia for severe cancer pain: A retrospective analysis of 60 patients

Lauri Kiehelä; Katri Hamunen; Tarja Heiskanen

doi:10.1016/j.sjpain.2017.04.073

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Spinal analgesia for severe cancer pain: A retrospective analysis of 60 patients

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From the journal Scandinavian Journal of Pain Volume 16 Issue 1

Abstract

Background and aims

Pain is highly prevalent in advanced cancer, and in some patients refractory to conventional opioid treatment. For these patients, invasive methods of pain relief should be considered. Spinal administration of opioids has been shown to be an effective alternative in refractory cancer pain. The aim of this retrospective study was to collect information on the use of spinal analgesia for cancer pain in Helsinki University Hospital.

Methods

A retrospective patient chart study of all cancer patients with spinal analgesia, either intrathecal or epidural, in a single academic center during a five year period (n = 60).

Results

Forty-four patients were treated with intrathecal (IT) and sixteen with epidural (EP) technique. The most common indication for spinal analgesia was pain refractory to systemic analgesics. Good analgesia was achieved in 50% and 70% of the patients in the EP and IT groups, respectively. The median daily systemic opioid doses prior to spinal analgesia were 874.5 mg and 730.5 mg as oral morphine equivalents in the IT and EP groups, respectively. The systemic opioid could be discontinued or significantly reduced in 83% of the patients. Morphine was used in all IT infusions and most EP infusions, mostly combined with bupivacaine 10mg (IT) or 66mg (EP). The median starting doses of morphine were 3 mg/day (IT) and 19 mg/day (EP) and were increased during titration 27% to 3.8 mg/day (IT) and 91% to 36.2 mg/day (EP). Clonidine (median 0.015 mg/day IT and 0.15 mg/day EP) and/or ketamine were used as adjuvants. The average titration time to stable analgesia was 7–9 days. Numbness in lower limbs was reported by 24% of the IT group. On average, catheters were placed 98 and 61 days before death in IT and EP groups, respectively. No serious complications occurred. Catheter dislocation occurred in 27% of all sixty patients during follow-up. Treatment was discontinued in 10 patients because of catheter dislocation (n =7) or local infection (n = 3).

Conclusions and implications

Spinal administration of opioids is a safe and effective method of pain management in patients with severe cancer pain and can greatly reduce the need of systemic opioids. We are implementing closer collaboration with oncologists to provide spinal analgesia to more patients and earlier to reduce suffering. Catheter dislocation led to discontinuation of spinal analgesia in 17% of the patients and we are evaluating new ways to prevent catheter dislocation. The initial median spinal opioid dose was too low in both groups, and we are now using higher initial doses. A common adverse effect was numbness of the lower limbs, regardless of the relatively low doses of spinal bupivacaine. We now use lower doses and introduce the intrathecal catheter higher at L1–2 to reduce motor blockade at the level of conus.

As an initial intrathecal infusions we suggest: morphine dose calculated using an oral to intrathecal ratio of 1:100 (unless the patient is elderly or already drowsy), clonidine dose 30μg/day and bupivacaine dose 7.5 mg/day.

Keywords: Refractory cancer pain; Spinal opioids; Intrathecal pain management

1 Introduction

In patients with advanced cancer, pain is highly prevalent [1]. In some patients the pain is refractory, i.e. not alleviated by conventional systemic opioid treatment with adequate adjuvant medication according to the WHO analgesic ladder [2]. For these patients, other analgesic methods should be considered, including neurosurgical interventions, intrathecal neurolysis or spinal analgesia.

Spinal administration of opioids has been shown to be an effective alternative in refractory cancer pain [3]. Complications, including infections, spinal hemorrhage and technical problems with catheters, such as occlusion or detachment, are rare [4]. Spinal administration of opioids may also reduce the incidence of opioid adverse effects compared to oral administration [5]. Adding a local anesthetic further increases the efficacy of spinal analgesia [6]. However, the role of spinal administration of opioids in refractory cancer pain has not been fully established, since few randomized, controlled studies on the subject have been published [7].

The aim of this retrospective study was to collect information on the use of spinal analgesia for cancer pain relief in a university hospital: the indications for spinal analgesia, duration of treatment, efficacy, and complications. Ultimately, the possibility of creating an algorithm for spinal analgesia in cancer pain was to be studied.

2 Methods

This was a retrospective study of all cancer patients with spinal analgesia (either intrathecal or epidural) in a single center (Helsinki University Central Hospital Pain Clinic) during a five-year period (from December 2004 to December 2009). The number of patients was 60, of which 44 were treated intrathecally (IT) and 16 epidurally (EP).

Data was collected, if available, from the medical records on the following details: indication for spinal analgesia, doses of opioid and adjuvant medication before and after starting spinal medication, time from catheter placement until stable analgesia (titration period), duration of spinal analgesia, clinical impression of efficacy, complications and possible discontinuation of spinal treatment before death. In addition, demographics, type of cancer, number of pain areas, main type of pain (nociceptive, neuropathic, visceral, mixed based on documentation in the medical records) and time of death were also noted.

When calculating oral and transdermal opioid equivalences, a ratio of morphine to oxycodone of 3:2 was used. [8]. Other conversion ratios used were methadone:morphine 1:4.7 [9] and transdermal fentanyl:morphine 1:100 [10], according to the practice in our clinic at the time.

In our clinic, a combination of spinal opioid and local anesthetic is commonly used, often in combination with ketamine and/or clonidine. The conversion ratios used for oral:epidural and oral:intrathecal were 30:1 and 300:1, respectively [11]. Since we had no routine algorithm for spinal analgesia, the analgesic drug doses and drug combinations were individually titrated for each patient. Antibiotic prophylaxis was not routinely used for catheter implantation.

For calculation of the conversion ratio from oral to intrathecal morphine, data from patients whose oral or transdermal opioids could be discontinued after spinal catheter placement were used.

3 Results

3.1 Indications and catheters

Gynecologic cancer was the most common reason for pain (Table 1). Pain was commonly located in the trunk and lower limbs. More than half of the patients reported pain in multiple locations. Epidural analgesia was chosen if the pain was located on the thoracic or cervical level (Table 2).

Table 1

Patient demographics and indications for spinal analgesia.

	Epidural (n = 16)	Intrathecal (n = 44)
Mean age (range), years	61(34–83)	54 (27–78)
Gender, male/female	7/9	15/29
Cancer diagnosis
Breast	2	6
Gastrointestinal	7	8
Gynecologic/genitourinary	1	19
Lung	5	2
Other	1	9
Indication for spinal analgesia
Inadequate pain relief	8	28
Adverse effects	1
Both	7	16

Table 2

Pain characteristics.

	Epidural (n = 16)	Intrathecal (n = 44)
Pain location
Trunk (abdomen, pelvis, back, chest)	16	43
Upper limbs	2	1
Lower limbs	3	21
More than one site of pain	6/16	28/44
Pain type^[a]
Nociceptive	4	6
Neuropathic		1
Visceral	4	5
Mixed	8	32

The most common indication for spinal treatment was inadequate pain relief with systemic analgesics. More than a third of the patients reported intolerable adverse effects in addition to inadequate pain relief. Only one patient was switched from systemic to spinal analgesia because of adverse effects alone.

The majority of the catheters were placed by a staff anesthesiologist of the Pain Clinic. Details on catheter placement and locations are given in Table 3. In two patients, epidural analgesia was chosen for technical reasons, i.e. intrathecal catheter placement was unsuccessful. More than one puncture for catheter placement was needed in 19% (EP) and 29% (IT) of the cases (Table 3). Our regular practice is to use a metal wire enforced epidural catheter as the IT catheter and to introduce the catheter 3–4 cm into the lumbar intrathecal space. All catheters were tunneled into the subcutaneous space on the ventral side of the abdomen.

Table 3

Catheter placement and location.

	Epidural (n =16)	Intrathecal (n = 44)
Catheter location	Cervical orthoracic: 12(75%)	L1/2: 1
	Lumbar: 2 (12%)	L2/3: 5
	NA: 2	L3/4: 28
		L4/5: 3
		n/a: 7
Problems with catheter application		2 patients: intrathecal catheterization was unsuccessful, therefore epidural analgesia
More than 1 puncture and/or comments on technical difficulties	3/16(19%)	13/44 (29%) (+above = 15)

3.2 Intrathecal and epidural drugs

The median (range) doses for drugs used in the IT and EP infusions are presented in Table 4. Morphine was the opioid used in all IT infusions. The median IT opioid dose was increased by 27% through the titration period. In three patients the opioid dose remained unchanged during titration, and in one case it was reduced. Data on the opioid starting dose was missing in two patients.

Table 4

Median (range) doses of spinal drugs before and after titration period.

	Intrathecal		Epidural

	Starting dose (mg/day)	Dose after titration (mg/day)	Starting dose (mg/day)	Dose after titration (mg/day)
Morphine	3 (0.6–21)	3.8 (0.72–34.6)	19 (9.6–115.2)	36.2 (16.3–258.7)
Bupivacaine	8.8 (4.8–24)	10 (0.96–86.4)	30 (24–480)	66 (24–460.8)
Clonidine	0.015	0.015	0.146	0.159
S-ketamine	2.5	3.5	19.2 and 48	21.6 and 48

In the EP group, 3 of the 16 patients were administered fentanyl, whereas morphine was used in 13 patients. In the EP group, the median morphine dose was increased by 91% from the beginning to the end of the titration period. The fentanyl dose was decreased in one and increased in one patient. In one patient data of the final dose was missing. In two cases, the initial fentanyl was later changed to morphine.

A local anesthetic (bupivacaine or ropivacaine) was added to all initial infusions. Data on local anesthetic doses was available in 42 of the 44 patients with IT infusions, and bupivacaine was used in all those infusions. In 10 patients (24%), the local anesthetic dose of the IT infusion was reduced during titration period because of leg weakness. Numbness of the lower extremities was reported as an adverse effect by 14 patients either during titration period or later. In 5 patients the dose of local anesthetic was decreased to resolve the problem.

In the EP group, 5 of 16 patients received ropivacaine, and 10 patients bupivacaine. In 1 patient data was missing. In contrast to the intrathecal group, the dose of local anesthetic was generally increased during titration (13 out of 16 patients). The median starting dose of ropivacaine was 166 mg/day (range 78.4–480 mg/day). The dose of local anesthetic was decreased during the titration period in three patients.

S-ketamine was initially added to eight IT infusions and two (12%) EP infusions. Twelve (27%) of the final IT infusions contained s-ketamine. Clonidine was added to the starting IT infusions in 9 patients, and was used in 20 (45%) of the final infusions at the end of titration period. In the EP group clonidine was used in eight patients.

3.3 Systemic opioid dose before and during spinal analgesia

At baseline, the median daily systemic opioid doses were 874.5 mg (range 0–2148 mg/day) and 730.5 mg (range 120–2668 mg/day) as oral morphine equivalents (MEQ) in the IT and EP groups, respectively (Table 5). Eighteen of 44 (41%) and 6 of 16 (38%) patients needed no regular systemic opioids after titration of IT or EP analgesia, respectively. Of the IT patients continuing on systemic opioids, 25% had their daily dose reduced by 50% or more (Fig. 1). The median systemic opioid dose after catheter placement and dose titration was 282 mg (range 0–7200 mg/day) MEQ in the IT group.

Figure 1

Reduction in systemic opioid dose after catheter placement and dose titration.

Table 5

Analgesics before spinal analgesia.

	Epidural (n = 16)	Intrathecal (n = 44)
Weak opioid	1	–
Strong opioid	16	43
Daily dose (MEQ)	730.5mg	874.5mg
NSAID	2	16
Paracetamol	10	19
Antiepileptic	8	27
Antidepressant	6	21
Combination (2 or more analgesics)	16	44
Other
Benzodiazepine	6	8

MEQ, oral morphine equivalent; NSAID, non-steroidal anti-inflammatory analgesics.

For the patients in whom systemic opioids were discontinued after IT catheter placement and titration (n = 18), the conversion ratio from systemic to IT opioid ranged from 18:1 to 400:1, being on average 152:1 (calculated in MEQ).

3.4 Titration period and duration of treatment

The time from catheter placement to stable analgesia (titration period) for the IT group varied from one day to a month, the average being a week (mean 7 days, SD 2.4 days). During the titration period, the infusion rate was changed up to 12 times. In the EP group, the titration period was longer than in the intrathecal group, with an average time of 9 days. The infusion rate was altered up to 10 times.

Intrathecal treatment was discontinued in two patients during the titration period. One patient did not want a new catheter after the first one had slipped out. One patient did not achieve adequate analgesia with intrathecal treatment and an epidural catheter was placed instead.

Long-term follow-up data was available for 88% and 82% of the patients in the EP and IT groups, respectively. After discharge from the university hospital, spinal analgesia was continued until the end of life in 66% of the patients whose follow-up data was available (50/60pts).

IT catheters were placed on average 98 days before death, and the average duration of IT treatment was 58 days (range 1–463 days). In one case, the catheter was placed only one day before death. Four patients had the catheter for over three months. Treatment was discontinued in 10 patients after an average treatment duration of 24 days because of catheter dislocation (n = 7) or infection (n = 3). After the unintentional IT catheter dislocation, two patients did not need further spinal analgesia, three patients did not want a new catheter and in two patients, the application of a new catheter was unsuccessful.

Epidural catheters were placed on average 61 days before death, and the average duration of treatment was 43 days (range 5–147 days). In three patients in the EP group, treatment was discontinued after median treatment duration of 20 days because of catheter dislocation, insufficient analgesia or switching to another analgesic method (chordotomy) (Table 6).

Table 6

Discontinued treatments. Data are number of patients.

	Intrathecal (n = 44)	Epidural(n = 16)
Treatments discontinued before death	10	3
Catheter dislocation	7	1
Infection	3	0
Insufficient analgesia	0	1
Switching to another analgesic method	0	1
Mean time from catheter placement to discontinuing treatment, days	24	20

3.5 Analgesic efficacy

At the end of titration period, 8 of 16 patients (50%) in the EP group and 31 of 44 patients (70%) in the IT group were considered to have achieved good analgesia, as recorded in the patient charts. Three patients in the IT group were specifically reported not to have gained any benefit from the treatment. The baseline opioid dose before IT treatment was 570 mg/day (median MEQ range 0–1680 mg/day) in patients who required no systemic opioid after catheter placement, and 665 mg/day (range 60–2148 mg/day) in patients who still had regular systemic opioid with the IT treatment. In the EP group, the initial median MEQ doses of systemic opioids were 461 mg/day (range 120–720 mg/day) and 931 mg/day (range 240–2668 mg/day) in patients without and with regular systemic opioids after EP treatment, respectively.

3.6 Complications

There were no fatal or serious complications. 75% of the patients in the IT group and 50% of the patients in the EP group experienced a minor complication or adverse effect (Table 7). The most common complication was catheter dislocation (16 of 60 patients, 27%). Three infections (5%) were recorded, two of them at the puncture site or in the subcutaneous tunnel. In one of these cases a bacterial culture from the tip of the catheter was positive. Numbness of lower limbs was common at an early phase of titration in the IT group (34% of the patients), most often resolved by a reduction of the dose of the local anesthetic. Three patients in the IT group had post puncture headache. Two patients in the IT group reported opioid withdrawal symptoms due to of systemic opioid dose reduction.

Table 7

Complications of spinal analgesia. Data are number of patients.

	Intrathecal (n = 44)	Epidural(n = 16)	All (n = 60)
Complications	33(75%)	8(50%)	41 (68%)
Catheter detachment	10	6	16
Lower extremity numbness	14	2	16
Infection	3	0	3
Postpuncture headache	3	0	3
Opioid withdrawal symptoms	2	0	2

4 Discussion

In this retrospective study of 60 cancer patients with poorly controlled pain, good or moderate pain relief was achieved in the majority of patients by switching from systemic to epidural or intrathecal opioid-based analgesia. The systemic opioid could be discontinued or reduced in the majority (83%) of the patients. Our results are in agreement of previous uncontrolled studies [3,12,13] reporting good efficacy of spinal analgesia in severe cancer pain.

In our hospital, cancer patients with poorly controlled pain are referred to the Pain Clinic mainly by oncologists. Our usual practice is first to optimize analgesia by noninvasive methods, e.g. adjuvant medication, and/or opioid switching (drug or route). If these methods fail, spinal analgesia is considered. After catheter placement in the OR recovery room, the patients are followed up on the oncological ward to titrate the spinal medication. We have an agreed clinical practice on the dosing of spinal drugs used but the attending anesthesiologist decides the exact doses. After achieving stable analgesia, the patient is discharged home or to a nursing home. Before discharge, the nurses of the Pain Clinic train the staff of the caretaking unit (nursing home, home care services etc.) to fill and change the cassette of the pump and to contact the Pain Clinic in case of trouble. Systematic follow-up has proven to be difficult because the patients come from a large area of different municipal areas and nursing homes, with patient record systems that do not communicate with the one used by our University Hospital.

All IT catheters are placed in the lumbar level and introduced 3–4 cm into the intrathecal space. This is an easy technique and does not require X-ray control. We use an opioid-based spinal analgesic regimen with a local anesthetic routinely added to all infusions. In an earlier study [14], adding bupivacaine to the infusion decreased the spinal opioid dose required, and increased patient satisfaction. However, the high number of patients experiencing numbness of lower extremities suggests that lower local anesthetic doses should be considered. In an earlier prospective study, levobupivacaine up to 25 mg/day did not cause numbness of lower limbs [12]. Limb numbness may not be as disturbing in bedridden patients may as in those who are ambulatory, but information to patients on this adverse effect prior to IT or EP catheter placement is necessary.

Clonidine is usually the first of second-line adjuvants, an α₂-agonist that has been shown to improve epidural morphine analgesia in cancer pain patients [15]. The exact indication and optimal dose of clonidine, however, remain unclear. The Polyanalgesic Consensus Conference (2012) suggested a starting dose of intrathecal clonidine of 40–100μg/day and a maximum dose of 600 µg/day [16]. In this regard, our initial clonidine doses have been low.

Another second-line adjuvant, ketamine, is an NMDA-antagonist that is assumed to improve analgesia and inhibit the development of opioid tolerance [17,18]. Case-reports on spinal ketamine have been published, but the exact role of ketamine in cancer pain is yet to be determined [19]. Ketamine may be used alone or in combination with clonidine in spinal infusions. Our study results do not allow any conclusions to be made on the effect of adjuvant drugs on the dose of the spinal opioid.

The exact conversion ratio from oral to intrathecal opioid remains unclear, even though an algorithm has recently been introduced [20]. We used data from patients whose systemic opioids could be discontinued after spinal catheter placement to estimate a conversion ratio. However, because these patients were few (18/44), and the combination of medications in the infusions varied, no definite conclusions on equipotent dosing can be made.

The median baseline MEQ opioid doses of the IT and EP patients were approximately similar, 874.5 mg and 730.5 mg, respectively, although individual variation between patients was high. The median opioid doses after titration were 5.5 times higher in the EP group compared to the IT group on patients whose systemic opioid was discontinued (18 and 6 patients, respectively). An intrathecal:epidural opioid equivalent ratio of 1:10 has been used in our clinic [11]. The present data are insufficient to change our current practice.

The IT and EP opioid doses were increased 27% and 91%, respectively, during the titration period. Spinal opioids were well tolerated. Only one patient in this study had some initial drowsiness, and no cases of respiratory depression or sedation were reported. Since the titration times to stable analgesia were quite long and the opioid doses were generally increased, a larger initial dose of the spinal opioid with local anesthetic and clonidine could shorten the titration period and the patient’s hospital stay. In a prospective study of 45 patients, the spinal opioid dose increase was much higher, 3-fold, when an oral to IT dose ratio of 100:1 was used, with no opioid-specific adverse effects reported [12]. In the same study, dose titration took in average 7 days, in which is in agreement to our data.

As an algorithm for initial intrathecal infusions we suggest

Morphine dose calculated using an oral to intrathecal ratio of 1:100 (unless the patient is elderly or already drowsy).
Clonidine dose at 30 µg/day
Bupivacaine dose at 7.5 mg/day

The complication and adverse effect rate, on the whole, was high, even though the complications were minor in nature. The most common complication was catheter dislocation. In our clinic, the catheter is usually tunneled subcutaneously from the puncture site to the lateral chest wall and connected to an external infusion pump. Tunneling alone is obviously insufficient in keeping the catheter in place, and more reliable methods for securing the catheter are needed. Alternatives are switching to subcutaneous port systems or implantable pumps. A systematic review of medication delivered by implantable intrathecal pumps for non-cancer pain found the rate of catheter dislocation to be 12%, compared to our 27% [21].

The limitations of this study are the small number of patients and its retrospective and observational nature. The small number of patients in our sample probably reflects both the unfamiliarity of spinal analgesia among health care providers as an advanced method of treatment for cancer pain, and the perceived limited availability of the method. The total number of cancer patients who might benefit from neuraxial analgesia for intractable cancer pain is unknown. Figures ranging from 1% to 20% have been suggested [22,23]. In one study, 2% of cancer patients seen for pain consultation received an IT-catheter [3]. Calculated from the estimated number of cancer deaths in our hospital district (approximately 3300 per year), less than 0.5% of patients dying with cancer received spinal analgesia. In light of previous studies and estimates on the need of spinal analgesia for refractory cancer pain, this is too low.

In this study, 58 out of 60 patients achieved satisfactory analgesia after switching from systemic to IT or EP analgesia for cancer pain. In two thirds of the patients for whom long-term follow-up data was available, spinal medication was continued until death, suggesting an important role for the method even in long-term pain management. The switch from systemic to spinal analgesia in our patients was implemented at a fairly late stage of the cancer disease, approximately two to three months before death. In the future, a trial of spinal pain management at an earlier phase should be considered for cancer patients with severe pain to provide adequate pain relief for longer periods at the end of life. Close co-operation between physicians caring for terminal cancer patients and pain clinic anesthesiologists is needed to achieve this goal.

Based on the findings of this retrospective study, future changes in our hospital include consideration of spinal methods for pain relief at earlier phases of cancer pain, use of new catheter anchoring methods or implanted devices to avoid catheter dislocation. Higher initial spinal opioid doses and more vigorous dose titration will be implemented to reduce titration time and hospital stay. Catheter insertion at a higher spinal level and smaller doses of local anesthetics will be used to reduce lower extremity numbness.

In conclusion and in agreement with a recent similar study published in this journal [24], this study shows that spinal administration of opioids is safe, effective and can greatly reduce the need of systemic opioids. Patient selection, the right timing and dosing algorithms are still open for further studies.

Highlights

In many cancer patients, pain is refractory to conventional opioid therapy.
Spinal analgesia is a safe and effective in treating refractory cancer pain.
Catheter dislocation is a frequent problem with external pumps.
Systemic opioid could be discontinued or significantly reduced with most patients.

DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2017.06.001.

Itämerenkatu 16 A 13, 00180 Helsinki, Finland.

Ethical issues: As a retrospective study, no informed consent was asked. The study was approved by the Finnish Ministry of Social Affairs and Health.
Conflict of interest: The authors have no conflict of interest concerning the study, nor any financial interests.

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Received: 2017-03-01

Revised: 2017-04-04

Accepted: 2017-04-30

Published Online: 2017-07-01

Published in Print: 2017-07-01

Articles in the same Issue

https://doi.org/10.1016/j.sjpain.2017.04.073

Keywords for this article

Refractory cancer pain; Spinal opioids; Intrathecal pain management