A small percentage of patients with cancer pain suffer from refractory pain despite aggressive therapy. [1]Intra-spinal administration of opioids and local anesthetic agents may be helpful in such settings, but their use may be limited by side effects such as motor block and hemodynamic instability. [2,3]Clonidine is a centrally acting alpha2-adrenergic agonist with established analgesic effects [4,5]and has synergistic effects with spinal opioids [6,7]and spinal local anesthetics. [8,9]Epidural clonidine produces analgesia by a spinal mechanism in patients after surgery and in those with cancer pain, [10]and it appears to be an effective treatment for severe cancer pain in patients for whom other treatments are ineffective. [11].

Although the risk of acute withdrawal and rebound hypertension is well recognized with sudden cessation of systemically administered clonidine, [12]no such reports exist with regard to epidurally administered clonidine. We describe a case of acute withdrawal and rebound hypertension after abrupt cessation of epidural clonidine in a patient with intractable cancer pain.

A 49-yr-old man was diagnosed with metastatic adenocarcinoma of the pancreas. The patient was normotensive and did not have a history of alcohol or other drug abuse. Despite chemotherapy with 5-fluorouracil and gencitabine, increased tumor growth resulted in complaints of upper abdominal pain radiating through to the back. Pain management was further complicated by complaints of diffuse abdominal pain and intermittent constipation associated with long-standing irritable bowel syndrome. Treatment with escalating doses of sustained-release and immediate-release morphine failed to control his pain and exacerbated his constipation. A neurolytic retrocrural celiac plexus block with 40 ml of 100% anhydrous alcohol produced only minimal relief of the pain. A temporary thoracic epidural catheter was inserted at the T8-T9 interspace, and a combination of 0.125% bupivacaine and 40 micro gram/ml morphine administered at 12 ml/h resulted in adequate pain control. One week later, a subcutaneously tunneled thoracic epidural catheter was inserted. The patient's pain was successfully managed at home with this regimen for 6 weeks. Because of complaints of increasing diffuse abdominal pain and postural hypotension, the patient was readmitted for evaluation and pain control. After epidurogram confirmation of catheter placement in the epidural space, incremental increases of both the bupivacaine and morphine concentrations failed to produce adequate pain control with unacceptable lower extremity motor impairment and postural hypotension. An epidural infusion of clonidine was added in a concentration of 10 micro gram/ml and commenced at 20 micro gram/h. This resulted in satisfactory pain control, enabling a rapid reduction in bupivacaine and morphine concentrations. Pain control was deemed adequate and postural hypotension eliminated with a combination of 0.1% bupivacaine and 50 micro gram/ml morphine at 12 ml/h and 10 micro gram/ml clonidine at 3 ml/h. After 2 weeks with this regimen, we noted progressive outward migration of the tunneled catheter. We decided to replace the catheter with a long-term implantable epidural device.

Because of concerns for potential infection of the new device, before inserting it, we decided to remove the tunneled catheter and administer intravenous vancomycin for 24 h. The patient was given a hydromorphone patient-controlled analgesia device with a continuous infusion for pain control. In addition, a 0.2-mg clonidine transdermal patch was applied at the time of discontinuing the epidural infusion.

Two hours after discontinuation of the epidural infusions, the patient was noted to be more agitated. A further 2 h later, he became progressively diaphoretic and tremulous. Blood pressure was increased from 140/80 to 220/110 mmHg, and heart rate was 170 beats/min. During this period, the patient complained of chest tightness. An electrocardiogram showed sinus tachycardia with new left bundle branch block. Nifedipine (10 mg) was given sublingually without significant effect on blood pressure control. A presumptive diagnosis of rebound hypertension after clonidine withdrawal was made when pain control was reported by the patient to be satisfactory. Five hours after the epidural infusions were discontinued, the patient received 0.1 mg oral clonidine. The patient was transferred to the intensive care unit for observation and blood pressure control. On arrival in intensive care unit, the patient's blood pressure and heart rate were 220/100 mmHg and 160 beats/min, respectively. In addition, the patient was noted to be profoundly agitated and profusely diaphoretic. A second dose of 0.1 mg oral clonidine was administered, and agitation was treated with small, intravenous incremental doses of midazolam to a total dose of 5 mg. Over the next 4 h, the blood pressure and heart rate gradually stabilized at 140/90 mmHg and 90 beats/min. The patient was discharged from the intensive care unit 14 h later with blood pressure stabilized at 140/80 mmHg and heart rate at 95 beats/min. A repeat electrocardiogram showed resolution of the left bundle branch block, and there were no new ST segment changes. Cardiac enzymes were normal. The clonidine transdermal patch was discontinued after the long-term epidural catheter was placed, and the patient recommenced epidural infusions of bupivacaine, morphine, and clonidine. The subsequent hospital course was uneventful, and the patient was discharged home with satisfactory pain control on a continuous epidural infusion of 0.1% bupivacaine and 40 micro gram/ml morphine at 12 ml/h and 10 micro gram/ml clonidine at 3 ml/h.

The management of advanced cancer pain is sometimes difficult and may be improved by epidural infusion of varying combinations of local anesthetic, opioid, and clonidine. [11]Although epidural administration of clonidine is not approved by the Food and Drug Administration for long-term use in treating cancer pain, the drug may be used on a compassionate basis in individual cases. Approval for use was sought and obtained in this case. Clinical experience to date with intraspinal clonidine is largely based on postoperative analgesia studies, although Eisenach [11]reported on its long-term use in cancer pain. This and other clinical studies [13–15]suggest that intrathecal and epidural clonidine in combination with opioids is a suitable treatment for intractable cancer pain.

The major side effects reported with the use of epidural clonidine are hypotension and sedation. [11]Clonidine decreases blood pressure after epidural administration by actions in the spinal cord [16]and brainstem [17]and in the periphery. [18]alpha2-Agonists decrease blood pressure by producing a "partial sympathectomy" as a result of direct inhibitory actions on preganglionic sympathetic neurons in the spinal cord. [16]Spread of the drug to the brainstem, by either rostral circulation in cerebrospinal fluid or systemic absorption, further diminishes sympathetic nervous system activity by actions at cardiovascular centers. [19–21]Sudden discontinuation of systemically administered clonidine may precipitate a withdrawal syndrome consisting of headache, apprehension, tremors, abdominal pain, sweating, and tachycardia, [12]accompanied or followed by a rapid rise in blood pressure. [22]The mechanism of rebound hypertension appears to involve an agonist-induced downregulation of normally sympatholytic alpha2receptors with resultant hyperresponsiveness of central noradrenergic pressor pathways after abrupt cessation of alpha2-agonist treatment. [23,24].

To date, there are no reports of acute withdrawal or rebound hypertension associated with discontinuation of an epidural infusion of clonidine. It is unlikely that the hypertension observed in this case was attributable to discontinuation of the bupivacaine/morphine infusion because pain was adequately controlled at the time by the use of hydromorphone patient-controlled analgesia (boluses plus background infusion). Of interest in our case, acute withdrawal and rebound hypertension were observed within 4 h of stopping the epidural clonidine infusion. This is in direct contrast to the relatively delayed onset of 18–36 h of withdrawal commonly observed with cessation of systemic administration of the drug. We speculate that abrupt withdrawal of epidural clonidine resulted in a more rapid elimination of the drug from cerebrospinal fluid than systemically administered clonidine. This more rapid and earlier decline of cerebrospinal fluid drug level at both cardiovascular brainstem centers and at spinal cord preganglionic sympathetic neurons may account for the earlier withdrawal reaction and rebound hypertension observed with epidural clonidine discontinuation.

Treatment recommendations for rebound hypertension and acute withdrawal after sudden cessation of oral or parenteral clonidine therapy include aggressive treatment of severe hypertension by intravenous bolus injection of phentolamine and reinstitution of oral clonidine therapy (0.1–0.2 mg followed by 0.1 mg hourly as needed up to a maximum of 0.5 mg). Clonidine therapy subsequently may be tapered over a number of days. [12,22]Although there are no guidelines for the management of similar problems with epidural use, the onset of oral clonidine may be too slow to adequately manage the withdrawal signs and symptoms, and intravenous administration of clonidine may be preferable. In our case, after initial blood pressure control, continuous monitoring of the electrocardiogram, close observation of blood pressure in the intensive care unit, and continued treatment of hypertension with oral clonidine until epidural therapy was reinstituted, proved satisfactory.

Further research is required to investigate both the time when the problems of acute withdrawal and rebound hypertension become apparent on discontinuing therapy after continuous epidural infusion of clonidine and the most appropriate method to manage these problems. This case prompts the recommendation for cautious discontinuation and tapering of the clonidine dose if clonidine has been chronically administered.

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