Diltiazem for the Management of Malignancy-Associated Perineal Pain and Tenesmus

Introduction

Discussion

Here we present two cases demonstrating the successful use of oral extended-release diltiazem for malignancy-associated perineal pain. In the above cases, both patients had advanced disease, previously received resection, chemotherapy, and radiation for their primary cancer, and newly diagnosed or suspected recurrent disease at the time of the intervention. Despite different underlying malignancies (urothelial and colorectal), both patients had similar pain syndromes at presentation: pressure-like pain in the rectum with tenesmus. After initiation of diltiazem, pain scores improved and total daily opioid usage decreased. Both tolerated the addition of oral diltiazem to their analgesic regimen without adverse effects.

It is important to note that confounding analgesic adjustments occurred in both cases. In case one, gabapentin was titrated the same day that diltiazem was initiated. In case two, methadone was started within 24 hours of initiating diltiazem. The N-methyl-d-aspartate (NMDA)-receptor antagonism properties of methadone may have provided additional analgesic effect compared to previously used opioids. ¹ Additionally, methadone metabolism may have been inhibited by diltiazem, a CYP3A4 inhibitor, resulting in a more potent therapeutic effect. ¹ Despite these confounders, we feel that diltiazem played a significant role in the dramatic pain relief for both patients. The slight dose titration of gabapentin in case one is unlikely to solely account for the dramatic improvement observed. Patient two suffered from two distinct types of pain: a “pressure” pain and a “stabbing” pain; the pressure pain resolved completely after starting diltiazem. The patient continued to require multiple doses of hydromorphone 12 mg orally every day for the stabbing pain for several weeks.

Perineal pain accounts for approximately 8% of all cancer-associated pain syndromes, most frequently occurring in patients with advanced colorectal, genitourinary, and prostate cancers.^2,3 The pain syndrome is frequently described as “tight,” “aching,” “drilling,” or “pressing” located deep within the rectum or pelvis ⁴ and often associated with rectal tenesmus and urgency.^3–5

Symptoms occur most commonly as a result of tumor recurrence, or postsurgical resection, or radiation injury.^3–6 In this population, pain and defecation issues often significantly impact quality of life.^5,7 Such symptoms can be quite difficult to manage despite utilization of currently available therapies including oral analgesics, radiation and interventional techniques.^3,4,8

CCBs are a chemically diverse group of medications, most well known for their cardiovascular benefits.^9,10 They are also beneficial in the treatment of noncardiovascular diseases such as Raynaud's, migraine, pulmonary hypertension, and esophageal spasm.^9,10 These medications exert their effects by blocking the L-type calcium channel located in both vascular and nonvascular smooth muscle. ⁹ Calcium channel blockers can be divided into two main classes, dihydropyridines and nondihydropyridines, with the class-specific physiologic effects resulting from their relative selectivity for L-type receptor located within certain tissues types. ¹¹ Diltiazem, a nondihyropyridine, causes less potent vasodilation, greater cardiac conduction and contractility depressive effect, and more frequent constipation side effect compared to dihydropyridines. The palliative care patient may be vulnerable to the constipating and vasodilatory effects of CCBs as this population is often plagued by gut hypomotility, opioid-induced constipation, volume depletion, and peripheral edema.

In the gastrointestinal tract, CCBs are potent inhibitors of intestinal smooth muscle contraction. The proposed mechanism of this effect includes calcium regulation within the smooth muscle cell moderating the excitation–contraction coupling process, as well as modulation of acetylcholine release from gastrointestinal tract neurotransmitters. ¹² As a result, CCBs have been shown to decrease large bowel motility, ¹³ reduce rectosigmoid intraluminal pressures and tone,^13–15 as well as diminish anal sphincter tone. ¹⁵

This knowledge has led to the use of CCBs in the management of pain syndromes of the lower gastrointestinal tract. In the only known report of CCB use in malignancy-associated perineal pain syndromes, McLoughlin et al. ¹⁶ described the use of oral nifedipine for the management of advanced cancer-related tenesmus resulting in improved symptoms of frequency and urgency in three of the four described cases after initiating a sustained-release nifedipine preparation at doses of 20–40 mg daily. Similarly, topical diltiazem has been recommended as first-line therapy for conservative management of chronic anal fissure. ¹⁷ Topical diltiazem and nifedipine have been shown to improve pain related to thrombosed external hemorrhoids and post-hemorrhoidectomy pain.^18,19 Oral diltiazem has been recommended as second-line therapy for the management of proctalgia fugax related anorectal pain.^20,21 There are no studies comparing the different CCB classes for use in these pain syndromes.

These cases, as well as the results of CCBs for use in other similar malignant and nonmalignant pain syndromes, suggest that oral diltiazem can be effective as an adjunct therapy for management of chronic malignancy-associated perineal pain, specifically with characteristics of pressure-type pain and tenesmus. A trial of the immediate-release preparation with transition to the long-acting preparation, if well tolerated, worked well in both of our cases. Further study assessing the use of oral calcium channel blockers in advanced malignancy-associated chronic perineal pain is warranted. Further study comparing the different CCB classes in this population would also be beneficial.