Multimodal intrathecal analgesia in refractory cancer pain

1 Introduction

Cancer pain impacts all aspects of patients well-being. Although cancer pain treatment has been improved, it is often inadequately treated, despite it being a major fear and concern of many patients [1]. Failure to respond to treatment not only impacts cancer pain but is also associated with depression, morbid mood and reduced quality of life [2]. Management of pain related complications with additional hospital admissions are of major health and economic concern in this growing population.

The prevalence of cancer pain has been reported to be as high as 60–70%, particularly in the terminal phases of the disease. After cure, chronic pain may still be around 21–46% [3]. This high prevalence in combination with an increasing cancer survival rate makes this a growing population that requires extensive pain modulation. The majority of this population (85–90%) can be treated effectively with analgesics following the Guidelines of the original World Health Organisation (WHO). Unfortunately 10–15% of the patients suffer from severe and refractory cancer pain and require additional pain management modalities [4].

In 1973, specific opioid receptors were discovered in the substantia gelatinosa of the spinal cord [5], followed by the first intrathecal injection of morphine [6]. Spinal opioids exert their analgesic effect by reducing nociceptive transmission in the dorsal horn of the spinal cord. Since the late 1980s, IT analgesic therapy has become an alternative for oral and parenteral pain treatment with opioids.

The implantation of an IT drug delivery system offers many advantages by improving analgesia with reduction of systemic or cerebral side effects compared to oral or parenteral opioids [7]. Because IT opioids are still associated with side effects like respiratory depression, opioid dose escalation, granuloma formation, pruritus and myoclonus, a wide variety of drugs are currently being used either single, or in a combination to optimize the therapeutic benefit. Non-opioids like bupivacaine [8, 9], clonidine [10], ziconotide [11, 12], ketamine [13], baclofen and ketorolac have been used neuraxial to minimize these opioid associated side effects.

Multimodal therapy in perioperative analgesia has become common practice. Combinations of different analgesics, acting at various points in the neurochemical pathway results in additive analgesia. This synergistic effect allows a reduction in the individual drug dose and thus lower the incidence of medication-related adverse effects. Unfortunately, multimodal IT analgesia for intractable cancer pain is not common practice. Tumber described a case in which severe cancer pain was controlled by IT infusion of morphine, bupivacaine and clonidine but no large case series are published [14].

Single use of clonidine, an α 2-adrenergic agonist, has shown to provide effective reduction in intractable cancer pain, particular in neuropathic type of pain [10]. The use of clonidine is limited as well, because of potentially side effects like hypotension, bradycardia and sedation.

In this retrospective research, the trialling combination of morphine, bupivacaine and clonidine was investigated in a group of terminal patients with refractory cancer pain, in order to gain a preliminary insight in effectiveness of this regime of multimodal analgesia in attenuating cancer pain and side effect profile.

2 Methods

3 Results

Nine patients had intrathecal cancer-pain treatment during the year from August 2012 to August 2013. The patients were between the 48 and 72 years of age with a male–female ratio of 5:4. Primary tumour location was pancreatic (4), urothelial (3) and prostate (2). Primary pain was considered neuropathic (n = 2) or mixed neuropathic-nociceptive (n = 7) and in 60% of the study population the cancer was disseminated. Included patients with pancreatic cancer were anatomically unsuitable for a plexus coeliacus or nervus splanchnicus blockade as primary invasive analgesic procedure. Of these patients, one had a para-aortic tumour mass and the other patients had locally advanced tumour growth in the truncus coeliacus.

The average NRS score before initiating ITT was 8.2 with a NRS score between 6 and 9. The mean daily morphine use was 358 mg plus non-opioids before ITT. Four patients used 1 non-opioid and 3 other patients used a combination of 2 non-opioids besides the oral opioids. Inadequate pain control was the main reason for initiation of ITT. Mean baseline NRS-score was 8.2. Demographic information of the included patients is shown in Table 1.

After initiating ITT, the average follow-up period was 11 weeks (2–29 weeks) during which 3 patients died within a month. All patients included in this study received a combination of intrathecal morphine, bupivacaine and clonidine with a daily basal morphine dose range of 1.4–4.8 mg/day (mean 4.1 mg/d). Daily received bupivacaine ranged from 9 to 16.2 mg/day (mean 11.4 mg/d) and clonidine ranged from 57.6 to 345.6 mcg/day (mean 142.4 mcg/d).

After initiation of ITT, all patients were free of pain with a mean NRS-score of 2.4 (T1) and this remained as such until hospital discharge (NRS 2.3). Daily dose of IT medication was gradually increased (Table 2). Patients were admitted in hospital for a mean of 6 days (2–14 days). During this time, medication adjustment took place in accordance with patients NRS-scores and side effects. No severe adverse events, defined as hypotension requiring inotropes, respiratory depression or neurological deficits were observed. Three patients experienced mild, clinical insignificant hypotension which resolved after clonidine dose adjustment. Mild lower extremity weakness occurred in three patients. All patients were still able to walk after initiating the ITT. Because of the of this lower extremity weakness, the bupivacaine dose was adjusted in two patients hereafter the sensation of weakness gradually decreased. Nausea and urinary retention occurred in 2 patients. Both patients with urinary retention received a urinary catheter for 4 days. They were discharged from hospital without a catheter a demeure. There were no signs of meningitis, neurologic sequela, sedation, pruritus, infection or catheter dislocation (Table 3).

After hospital discharge, there was a gradual increase in NRS-score, with an average rating score of 3.0. Six patients were still free of pain, 1 patient had a NRS-score of 6 (Fig. 1 ). One patient was discharged to a hospice facility, specialized in terminal health care, were no pain scores were taken and the NRS-score of one patient was not recorded. All patients were hemodynamically normal and stable with no signs of hypotension. Of the 3 patients who experienced mild lower extremity weakness after initiation of ITT, only one patient still experienced mild lower extremity weakness as a result of conus compression by tumour.

Fig. 1

NRS scores off all 9 patients during different time intervals. T0: NRS score before initiating ITT. T1: NRS score just after initiating ITT. T2: NRS score at hospital discharge. T3 mean NRS score in the ambulant setting. T4: the last NRS score taken before death occurred.

Before dying the mean NRS-score was increased to 4.1 by which 5 patients were still free of pain, 2 patients reported NRS-score of 6 and 1 patient reported a NRS-score of 7. The NRS score of one patient admitted in a hospice was not taken.

Opioid dose escalation with an increasing OEI and NRS-score >4 was seen in 2 patients. Both patients showed the opioid dose escalation in the last days of the ITT, without any sign of catheter dislocation. All other patients showed reaction by increasing the IT opioid dosing without showing side effects.

Further observations during the multimodal IT-therapy showed reduced psychological distress in all patients. With reducing NRS-scores, patients were finally able to process the course of disease. By processing the disease, most patients also start worrying (N = 8), had concerns about family (N = 3), or had problems dealing with the cancer (N = 1)

4 Discussion

In this retrospective case series, multimodal IT analgesia consisting of morphine, bupivacaine and clonidine show a remarkable reduction of pain in terminal cancer patients with otherwise intractable cancer pain. In accordance with literature, most of our included patients experience neuropathic or mixed neuropathic-nociceptive cancer pain [7]. As a result, systemic or neuraxial delivered opioids fail to reduce pain, despite large doses with concomitant side effects like respiratory depression, opioid dose escalation, granuloma formation, pruritus or myoclonus.

Morphine combined with clonidine administered epidurally seemed to be particularly effective in intractable neuropathic cancer pain, although hypotension was reported as substantial side effect [10]. Adding bupivacaine to morphine improved analgesia and reduced side effects compared to morphine alone [8]. Bupivacaine blocks nerve impulses and provides a degree of nociceptive, sensory and motor nerve block. Intrathecal starting dosage below the 30 mg/day are not associated with bupivacaine induced side effects [15]. Evidence suggest that bupivacaine acts synergistically with morphine, reducing the need for increasing IT morphine dose [9, 15]. Also in chronic noncancer pain patients, adding IT bupivacaine to morphine attenuates opioid dose escalation [16].

With ITT, drugs are delivered close to their site of action in the central nervous system avoiding first-pass metabolism and blood–brain barrier. It may improve analgesia with a smaller dose and possibly achieve a reduction in systemic or cerebral side effects compared to oral or parenteral opioids alone. By delivering multiple medication, acting at various points in the neurochemical pathway, multimodal analgesia can provide additive analgesia and can potentially reduce side effects as well.

Intrathecal therapy is used for many years. Nevertheless, there is still lack of quality evidence regarding the benefits and harms of this technique for intractable cancer pain. Small sample sizes, heterogeneous characteristics in medication, dosages and route of neuraxial administration are among limiting factors [17]. A GRADE (Grades of Recommendation, Assessment, Development and Evaluation)-type meta-analysis showed a weak strength of recommendation for administration of neuraxial analgesics based on four included randomized controlled trials [18, 19]. Unfortunately the studies were small and with a high degree of heterogenicity. Another systemic review recommended intraspinal techniques for pain management in cancer patients, although they did formalize the development of their recommendation [20].

The placement of an intrathecal catheter requires expertise. Possible complications are related to insertion, device malfunction and medication related complications [17]. Ways to reduce common catheter related complications are outlined by Follett and colleagues [21]. They found reduction of complications by gaining dural excess in mid-to-upper lumbar region, precise catheter anchoring and tunnelling techniques. Systemic antibiotic prophylaxis, attention to pump pocket location and surgical wound closure were among other factors reducing complications [21].

In our population an ITT combination of morphine, bupivacaine and clonidine resulted in a remarkable reduction of pain. No severe adverse events did occur. Clinically insignificant hypotension and mild lower extremity weakness occurred at start of ITT. After dose adjustment these side effects were diminished. Two patients experienced an opioid dose escalation in the last days of ITT, not an uncommon side effect before dying. Recommendation of starting doses is shown in Table 4. This retrospective case study gives a preliminary insight in the effectiveness of multimodal IT analgesia. Further research by means of large prospective conducted randomized controlled trials are needed to verify these conclusions. Because of the promising results of this study we are now performing a prospective cohort study to assess the effectiveness of this multimodal IT analgesia regime as well as the impact of multimodal ITT on psychological aspects.

5 Conclusion

Multimodal intrathecal medication consisting of morphine, bupivacaine and clonidine is effective in treating refractory cancer pain in the terminal phase of disease and has an acceptable side effect profile. Consequently, synergistic analgesia is produced in which the IT dosage can be reduced compared to monotherapy and thereby reducing potential side effects.

Highlights

• 10% of cancer pain patients are not effectively treated according to WHO-guidelines

• Multimodal intrathecal analgesia is effective in treating refractory cancer pain

• No severe adverse events occurred in our study with multimodal intrathecal therapy