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Abstract |
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We performed a double-blinded, randomized, controlled trial in 15 patients to determine the efficacy of intrathecal morphine or clonidine, alone or combined, in the treatment of neuropathic pain after spinal cord injury. The combination of morphine and clonidine produced significantly more pain relief than placebo 4 h after administration; either morphine or clonidine alone did not produce as much pain relief. In addition, lumbar and cervical cerebrospinal fluid (CSF) concentrations, sampled at these levels at different times after administration were examined for a relationship between pain relief and CSF drug concentration. Lumbar CSF drug concentrations were initially several orders of magnitude larger than those in cervical CSF. After 1–2 h, the concentrations of morphine in cervical CSF markedly exceeded those of clonidine. The concentration of morphine in the cervical CSF and the degree of pain relief correlated significantly. We conclude that intrathecal administration of a mixture of clonidine and morphine is more effective than either drug administered alone and is related to the CSF-borne drug concentration above the level of spinal cord injury. If there is pathology that may restrict CSF flow, consideration should be given to intrathecal administration above the level of spinal cord damage to provide an adequate drug concentration in this region.
Implications: Neuropathic pain after spinal cord injury is very difficult to control adequately by using currently available techniques. We have performed a placebo-controlled, double-blinded study demonstrating that administration of a combination of morphine and clonidine into the spinal fluid can provide substantial pain relief in some people with this type of pain.
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Introduction |
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Neuropathic pain is a frequent and debilitating accompaniment of spinal cord injury (SCI). This type of pain, in which there is loss or modification of normal afferent sensory inputs, is notoriously resistant to currently available modes of treatment and highlights the general lack of understanding of underlying neuropathic pain mechanisms (1).
Various approaches have been used for the treatment of neuropathic SCI pain with varying degrees of success, including using simple analgesics, anticonvulsants (2,3), tricyclic antidepressants (2), systemically administered local anesthetics or their congeners (4,5), spinal cord stimulation (6), and neural blockade procedures. Although these treatments are often used empirically, there are few systematic controlled studies of efficacy and, in those that have been done, treatment has sometimes been shown to be ineffective (3).
There is an increasing number of reports demonstrating the effectiveness of intrathecally administered drugs in the management of a variety of pain problems (7). The intrathecal route has the advantage of delivering an effective drug close to its presumed site of action with minimal systemic side effects from the small doses used (7). Therefore, intrathecal administration of an effective drug presents a logical choice for the treatment of neuropathic pain. However, there are no controlled studies using this mode of administration for the control of neuropathic pain after SCI. Where this technique has been described, it has been largely confined to case reports (8,9) and provides no rationale for using these drugs in terms of effective doses, side effects, and other important variables.
A number of reports indicate that spinally administered opioids are effective with minimal side effects in patients with cancer and chronic noncancer pain, some of whom appeared to have neuropathic pain (7). Although it has been demonstrated that neuropathic pain may be opioid sensitive (10), the doses required by systemic administration for satisfactory control often result in unacceptable side effects. Further evidence using an animal model of neuropathic pain after SCI suggests that intrathecal administration of opioids may be effective for this type of pain (11).
Evidence from both basic and clinical studies indicates that clonidine is effective in the management of pain, including neuropathic pain (12). Clinical studies have confirmed the effectiveness of spinal clonidine in the clinical setting in the control of neuropathic pain associated with cancer (13,14) and postoperative pain (15,16). Although there is preliminary support for the effectiveness of a single epidural dose of clonidine in the management of neuropathic pain after SCI (17), as yet, there are no studies that investigated the effectiveness of different doses and continuous infusions of intrathecal clonidine for the treatment of this type of pain. There is also evidence that morphine and clonidine may have a synergistic action in reducing pain (18). This means that a combination of the two drugs may be more effective than either drug alone with a possible reduction in side effects associated with their administration.
The aim of this study was to use a randomized, double-blinded, placebo-controlled design to evaluate the efficacy of intrathecally administered morphine and clonidine, both alone and in combination, in the treatment of neuropathic pain after SCI. Furthermore, we sought to determine the time-course concentrations of these drugs in lumbar and cervical cerebrospinal fluid (CSF) and to determine whether the CSF drug concentration was correlated with the pain relief obtained.
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Methods |
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The study protocol was approved by the institutional medical ethics review committee. Those eligible to take part in the study were patients who had neuropathic pain after SCI and who were unresponsive to other treatment. Patients were not considered for the study <4 wk after their injury and until they had undergone a trial of other drugs used for the treatment of neuropathic pain after SCI. These included oral opiates (morphine, methadone, codeine, pethidine, buprenorphine), anticonvulsants (valproate, carbamazepine, gabapentin), mexiletine, clonazepam, tricyclic antidepressants (amitriptyline, doxepin), nonsteroidal antiinflammatory drugs and, in one patient, dextromethorphan. The earliest entry point for any patient was 7 months after the onset of pain. Patients who had SCI at or above C-4 were excluded from the study because of the risk of respiratory arrest. Other exclusion criteria included preexisting hypertension, angina, congestive cardiac failure, active urinary tract infection, and age >80 yr. If possible, participants gave written informed consent. Verbal informed consent was obtained from patients unable to write.
Fifteen patients were enrolled in the study. The mean age was 50 (range 26–78) yr. Neuropathic SCI pain was classified into at-level and below-level neuropathic pain as defined below (see "Discussion"). Thirteen subjects had below-level neuropathic pain and four had at-level neuropathic pain. Three subjects had both types of pain.
Physical examination was performed as part of the assessment to determine the presence or absence of sensory disturbance including loss or reduction in sensation to pin prick and light touch or increased responsiveness to pin prick and light touch (mechanical hyperalgesia and allodynia).
Subjects using morphine or clonidine before entry to the study were required to stop taking these at least one week before entering the study. After admission to the procedure room, a cannula was inserted for venous access and a catheter was inserted into the lumbar intrathecal space. When it was confirmed that the catheter was within the intrathecal space by free aspiration of clear CSF, it was secured by tape and the subject placed in a semirecumbent position. The intrathecal catheter remained in situ for up to 6 days unless there were signs of infection.
Administration of either placebo (saline), morphine, or clonidine was commenced depending on the sequence randomly allocated to the subject. On the first day, the subject received the first drug (saline, 0.2–1 mg of morphine, or 50–100 mcg of clonidine). The initial dose of morphine was calculated according to the prior use of opioids. If the patient was opioid naive, then 0.5 mg was administered with the exception of one subject who commenced on 0.2 mg. If the patient was on regular opioids, then the dose was calculated as 1/100 of the daily IM dose or 1/200 of the daily oral dose.
Blood pressure, respiratory rate, and pulse rate were monitored in the procedure room for 6 h. The subject received supplemental oxygen via a face mask (8 L/min) or via nasal prongs (2 L/min) depending on pulse oximetry (
94%). Pulse oximetry was used in the procedure room and continued on return to the ward for a further 12 h after the procedure.
If there was no pain relief or adverse side effects (sedation or effect on respiratory function), the subject received an increased dose of the same drug (1.5 times the initial dose) on the second day and two times the initial dose on day 3. Sedation was assessed by using a 4-point scale: 1 = mild, occasionally drowsy, easy to rouse; 2 = moderate, frequently drowsy, easy to rouse; 3 = severe, somnolent, difficult to rouse; 4 = normally asleep, easy to rouse. Respiratory function was assessed by monitoring respiratory rate, end-tidal CO2, and oxygen saturation. No further dose increases of a drug were contemplated if the sedation score reached 3 or if oxygen saturation could not be maintained >94%. When a response was obtained to the drug (either satisfactory pain relief or side effects), testing of the next drug began the next day. Eight subjects were administered clonidine by bolus and infusion rather than as a single bolus dose.
After administration of saline, morphine, and clonidine and attainment of either satisfactory pain relief or side effects with each drug, the subject received a mixture of morphine and clonidine. The subject received one-half the final dose of morphine and one-half the final dose of clonidine that were administered in the previous part of the study.
During the course of the study, subjects were allowed to continue oral acetaminophen (paracetamol). Severe pain requiring stronger analgesia during the course of the study, but outside the intrathecal testing period, was managed with rescue doses of oral dextromoramide 5–10 mg every 2–4 h as required. All except two patients required rescue analgesia. In two patients, 1 g of acetaminophen was sufficient to obtain adequate analgesia. In the remainder, 5–40 mg of oral dextromoramide was required.
In all of these procedures, the subject was observed and assessed by an investigator who was blinded to the test medication being used. The investigator also assessed the subject for the severity of pain immediately before commencing the procedure and each hour in the procedure room. Tests used for assessment of pain included a numerical pain rating scale (0–100), a numerical pain relief score (0–100), and a verbal pain rating (none, mild, moderate, severe, or very severe). Any side effects were also noted and end-tidal CO2, nausea scale (0–10), and sedation score were recorded.
Seven subjects underwent blood and CSF sampling for measurement of drug concentrations. CSF samples (2 mL) were withdrawn concurrently by using a 24-gauge needle under local anesthesia, from a lumbar (L3-4) and from a cervical (C-7/T-1) site to determine the drug migration. Each subject had CSF and venous blood samples (5 mL) withdrawn after administration at up to three of the randomly allocated times: 10, 20, 30, 60, 120, 180, and 240 min after administration. Samples were immediately frozen and stored at -18°C until assayed. CSF and blood concentrations of morphine and clonidine were determined by using gas chromatography-mass spectrometry after solvent extraction by using the method described previously (19).
To compare groups, the proportion of those who had a positive response at any time during the assessment (defined as 
50% pain relief on either the pain relief scale or as calculated from numerical pain ratings) was determined in each group. The proportions of positive responders in each group were then compared by using 
2 test. A P < 0.05 was accepted to indicate significance.
To determine the effectiveness of different drugs, comparisons were made of the relief obtained at the time of maximal effect after drug administration. Statistical analysis was performed by using a Student’s t-test. A P < 0.05 was accepted as significant.
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Results |
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Of the 15 subjects tested, five responded positively (defined as
50% relief from baseline pain score before drug administration) to intrathecal administration of saline, three responded positively to intrathecal administration of the final incremental dose of clonidine, four responded positively to intrathecal administration of the final incremental dose of morphine, and seven responded positively to intrathecal administration of the mixture of morphine and clonidine (one-half of the final incremental dose of each drug) (Figure 1). Of the three that responded to clonidine, two received clonidine by infusion and one as a bolus injection.
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When responses were divided into different types of pain, it was found that two of four subjects with at-level neuropathic pain responded positively to the mixture of morphine and clonidine, whereas only five of 14 subjects of those with below-level neuropathic pain responded positively (Figure 1). The difference in these proportions did not reach statistical significance (Fisher’s exact test).
Intrathecal administration of morphine resulted in a mean reduction in pain levels to 80% (SEM ± 9%) of the baseline pain score before drug administration (Figure 2). Intrathecal administration of clonidine resulted in a mean reduction in pain levels to 83% (SEM ± 10%) of the baseline pain score before drug administration (Figure 2). These reductions in pain levels were not significantly different from the relief obtained after saline administration (100% ± 4% SEM). Intrathecal administration of the mixture of morphine and clonidine resulted in a mean reduction in pain levels to 63% (SEM ± 10%) of the baseline pain score before drug administration (Figure 2). There was a significant difference in the relief obtained with the mixture of morphine and clonidine compared with placebo at the same time point (P = 0.0084).
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The median minimal effective dose (defined as the dose that provided satisfactory pain relief (or dose to side effects) for morphine was 0.75 mg (range 0.2–1.5 mg) and in those who received a bolus injection, the median dose for clonidine was 50 µg (range 50–100 µg). In those who received an infusion of clonidine (n = 8), the dose administered was between 300 and 500 µg administered over 6 h.
The most common side effects after morphine administration in those with SCI were pruritus, oxygen desaturation, sedation, nausea, and hypotension (>15% decrease in blood pressure) (Table 1). The most common side effects after clonidine administration were hypotension, nausea, sedation, oxygen desaturation, and dry mouth. Of those who received saline, 13% experienced sedation and 13% had oxygen desaturation. The most common side effects after the administration of the mixture were hypotension, oxygen desaturation, pruritus, dry mouth, and sedation. Using the mixture did not result in a marked reduction in the incidence of side effects.
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Very large concentrations of morphine and clonidine were found initially in the lumbar CSF; concurrent concentrations in cervical CSF were several orders of magnitude smaller. Clonidine cervical CSF concentrations remained small or undetectable; however, morphine concentrations increased, reaching a maximum at approximately 1.5–2 h. (Figure 3). Concurrent plasma concentrations of clonidine were essentially undetectable (ca <0.1 ng/mL) throughout; those of morphine ranged from being undetectable to a maximum of approximately 7 ng/mL in one patient with most values being between 1 and 3 ng/mL. There was a significant correlation between the amount of pain relief obtained after the administration of the mixture of morphine and clonidine and the maximal concentration of morphine in the cervical CSF (r = 0.75, t = 2.74, df = 6, P < 0.05). There was no correlation between pain relief and the concentration of clonidine in the cervical CSF or the concentration of either morphine or clonidine in the lumbar CSF.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Neuropathic pain after SCI presents a difficult management problem. Intrathecal administration of drugs provides an alternative method of drug delivery and can produce relief in patients who are unresponsive to other treatment approaches. Our study suggests that intrathecal administration of a mixture of morphine and clonidine can provide relief in a proportion of people with neuropathic SCI pain when other treatment approaches have failed. Although this was previously suggested from case reports, it is the first time that the efficacy of these drugs has been investigated in a randomized controlled trial. There are a number of other conclusions that can also be drawn from the study.
First, a mixture of both morphine and clonidine appears to be more effective than either drug administered alone. Although there were patients in the study who did report satisfactory relief with either or both of these drugs, the group data do not reveal a significant difference in the amount of pain relief obtained from either morphine or clonidine and placebo. In this study, one-half the minimum effective dose of each drug was administered in the combination of morphine and clonidine and this mixture resulted in a significant reduction in pain compared with placebo. This suggests that supraadditive or synergistic effects could occur when the drugs are administered in combination.
Several other animal (18,20) and clinical (15) studies suggest that clonidine and morphine may have a synergistic action when administered spinally (21). The actual mechanisms responsible for this synergism are unknown; however, it has been suggested that opioids and 
2-adrenoceptor agonists act functionally on distinct, but complementary, descending inhibitory pathways and spinal systems. Our findings support previous evidence that these drugs have a synergistic action in producing analgesia and suggest that consideration should be given to the coadministration of these drugs for treatment of this type of pain.
Second, there is a suggestion from our study that types of pain may respond differently to drug administration. Neuropathic pain after SCI can be divided into two subtypes of pain according to site and probable mechanisms (22). The first of these is at-level neuropathic pain that may be caused by damage to nerve roots or to the spinal cord itself and results in spontaneous or evoked sharp, shooting, stabbing, burning, or electric pain that is confined to the three dermatomes adjacent to the level of spinal cord damage. The second type is below-level neuropathic pain that presents as a spontaneous, burning, stabbing, shooting, or electric pain located diffusely below the level of injury.
It is difficult to make firm conclusions because of the small number of subjects in the subgroups and other factors that may influence outcomes. Nevertheless, there was a larger proportion of those with at-level neuropathic pain who obtained substantial relief of their pain. Animal studies using a model of at-level neuropathic SCI pain have demonstrated physiological changes at a spinal level that may be more readily accessed by spinally administered drugs (23). Furthermore, the neuropathic pain-like behavior in such a model is reduced after intrathecal, not systemic, administration of morphine and clonidine (11,24). Therefore, it appears that at-level neuropathic SCI pain may be more susceptible to drugs directed at a spinal level. In contrast, it has been demonstrated in humans that below-level neuropathic SCI pain is associated with changes at a thalamic level (25). Although it is not known whether these changes in the thalamus reflect changes occurring spinally, it is possible that supraspinal changes occur with neuropathic below-level pain and are relatively inaccessible to spinally administered drugs at doses that do not result in significant side effects.
Although intrathecal administration of morphine and clonidine resulted in substantial pain relief in a number of subjects, this treatment was ineffective for others. Part of the reason for the lack of effect in some subjects may be explained by the findings from the CSF sampling. The relatively large concentration of drugs in the lumbar CSF with small or undetectable levels in the cervical CSF suggests interference with CSF flow because of scarring around the site of spinal trauma. Furthermore, the greater hydrophilic character of morphine facilitates its distribution cephalad by bulk flow of CSF, whereas clonidine distributes more readily into tissues. Clearly, the inability of the drug to reach the required site of action (whether immediately above the cord lesion or supraspinal) means that it will be difficult or impossible to obtain adequate analgesia even with the administration of relatively large doses. This is supported by the finding that there was a significant correlation between pain relief and the concentration of drug in the cervical CSF. In fact, in one of the study subjects in whom lumbar administration resulted in a poor response, subsequent administration of the drugs at the cervical level resulted in good relief of pain. Therefore, it appears that in patients who have neuropathic pain after SCI, intrathecal administration of drugs should occur above the level of injury, if there is any evidence of obstruction to CSF flow. Further investigation, such as computed tomography myelogram may be helpful in determining whether this is likely before drug administration. It is noted that clonidine concentrations in plasma were uniformly undetectable; morphine concentrations were much smaller than those usually associated with pain relief (26).
In conclusion, intrathecal administration of morphine and clonidine appears to provide good relief of pain for a proportion of patients with neuropathic pain after SCI who are unresponsive to other interventions. Furthermore, the mixture of morphine and clonidine appears to have a synergistic action and is more effective than either drug administered alone. In those patients with neuropathic pain after SCI, consideration should be given to intrathecal administration of drugs above the level of SCI, if there is evidence of obstruction to CSF flow.
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Acknowledgments |
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Supported, in part, by the National Health and Medical Research Council of Australia.
The authors would also like to thank a number of people who were involved in the conduct of the study. These are Joan McClelland, Kathy Gustafson who monitored and assessed the patients, Bronwyn Fryirs and Li Huang who helped to set up and run the GC-MS assay and Drs. Winnie Hong, Andrew Muir, Mary Cardosa and Michael Hudspith for intrathecal catheterization and supervision of patients. We would also like to thank Dr. James Middleton and the staff of the Spinal Injuries Unit for their cooperation, advice and expert care of people with SCI during the time of their admission and testing.
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References |
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