Role of neuraxial drug delivery in cancer pain therapy

There is significant laboratory and clinical evidence that now should call into question our long-held beliefs on the best approaches to the management of cancer pain. Approximately 1.7 million patients are diagnosed and 0.6 million die each year with cancer in the USA [1]. Total national spending of cancer care is estimated at $125 billion in 2010. Although cancer is among the leading cause of death, overall cancer mortality has decreased steadily since the 1990s. Improved cancer treatment allows a greater number of people to survive longer; however, often cancer survivors are left with residual morbidity, including chronic pain. Pain occurs in approximately 50% of those with cancer [2]. The etiology of cancer pain is diverse and multifactorial. It can originate from the cancer treatment or from direct effects of the cancer itself. Pain can manifest as a result of mucositis, infusion-related pain, neuropathic pain, myalgias or arthralgias from chemotherapy or radiation-induced pain. Pain from cancer has a number of etiologies presenting as a varying degree of neuropathic and nociceptive characteristics. Regardless of the etiology, opioids are usually an integral part of the treatment [3].

Management of the cancer patient requires consideration of two elements: control of tumor growth/metastasis and management of pain secondary to cancer and its treatment. An extensive meta-analysis showed that cancer pain prevalence was 39.3% after curative treatment, 55.0% during anticancer treatment and 66.4% in advanced or terminal disease [4]. A component of this pain is associated with life-sparing radiation and chemotherapy-induced peripheral neuropathies, lasting >3 months in 30–70% of all cancer patients with the commonly used therapeutics [5].

Cancer pain management

Management of cancer pain is an imperative because of such pain’s negative impact upon quality of life and the adverse physiological events that can arise from the stress secondary to an unmanaged pain state [6]. Of equal significance, cancer survivors are living longer following their diagnosis. In one review, the proportion of persons with cancer who survived ≥5 years after diagnosis was 67% and trending upwards [7], which points to the necessity of cancer pain management for increasing intervals. The use of oral or transcutaneous opioid analgesics has been advocated as a standard of care to reduce the physiological consequences of stress and cancer pain ever since the publication and widespread adoption of the WHO (Geneva, Switzerland) ladder in 1986 [8]. This approach, without consideration to the impact on a patient’s well-being or disease impact, has never been thoroughly evaluated. Oral morphine is the common agent for managing cancer pain states [9], with typical dosing in the range of 100–250 mg/day, though dosing can be significantly greater for patients with severe pain [10]. Many pain management guidelines such as the CDC guidelines make exceptions for maximum recommended opioid dosing when used for cancer pain management [11].

Limitations of the current standard of pain management

Typically, opioids are titrated to effect with dose escalations common in the setting of disease progression or as tolerance develops. The WHO ladder was first published as a response to public health surveys that documented the generally inadequate approach to cancer pain. The goal was to establish an easy-to-use, stepwise approach to the escalation of opioids in severe cancer pain. Unfortunately, many patients are not referred to pain management resources early enough, exposing them early to the risks associated with high opioid doses. While oral opioids result in significant pain relief, more than half of cancer patients have insufficient pain control, and about a quarter die in pain [12]. Such failure reflects three issues: cancer pain arises from multiple sources and often is believed to involve to varying degrees a neuropathic component for which opiates are less efficacious and require higher dosing [13]; higher doses are accompanied by an increase in dose-limiting effects including peripheral (nausea, vomiting and constipation) and central (sedation, hyperalgesia and seizures) [14]; and opiate induced hyperalgesia may occur, reflecting an enhanced excitability leading to a worsened pain state [15]. As survival after a cancer diagnosis increases, opioid therapy, which was once limited to short-term palliative care, shifts to one of a more long-term treatment of chronic pain [16]. Therefore, the impact of opioids on cancer physiology is an important question to consider.

Effects of anesthetics & analgesics on the immune system & cancer survival

An intact, functioning immune system is indispensable for cancer survival. Multiple retrospective studies have found that anesthesia management can have profound impact on survival months or even years after the original cancer surgery [17,18]. These studies suggest that impairment of cell-mediated immunity is responsible for differences in the long-term cancer prognosis. Inhalation anesthesia is known to have significantly greater cell-mediated immune suppression than intravenous anesthesia [19]. Due to these concerns, anesthesia for oncological surgery has begun to move away from an inhalational/opioid-based approach to either an intravenous anesthesia with either low or no opioids being used as supplement, or a postoperative anesthesia-based pain management. When the immediate postoperative period is over, a handoff occurs from anesthesia to the primary oncologic treatment team. At that point, the primary treatment for pain reverts back to opioids as the primary analgesic with or without adjuvants. The known benefits of minimized opioid administration in the anesthesia-managed perioperative period are then at risk for being lost. Opioids are known to have immunological modulating effects [20]. There are multiple different influences that can impact cell-mediated immunity that can counteract cancer treatment, including the escalating systemic doses of opioids when used as the primary analgesic (Figure 1) [21].

Despite years of a broad-based consensus supporting opioids in the treatment of cancer-related pain, they have not yet been systematically examined for their safety, particularly in the treatment era of angiogenesis inhibitors and the growing use of immunotherapies.

Opiate effects upon tumor growth

It has become a working hypothesis among physicians working with cancer pain that peripheral opiates may facilitate tumor development and reduce long-term survival [22]. While a systematic literature review found insufficient evidence to draw conclusions regarding the association between opioid use and survival in cancer patients, the studies identified were not powered to assess the impact of opioids on survival as a primary end point [23–25]. Afsharimani et al. reviewed both clinical and nonclinical evidence and could not conclude that morphine was a safe analgesic in patients with cancer [26]. However, retrospective clinical studies have suggested that cancer patients managed with perioperative morphine displayed worse outcomes compared with those receiving nonopioid regional anesthetic management or epidural analgesia [27,28], leading to concerns that opioids can promote tumor progression and relapse [29]. A prospective randomized study concluded that there was no survival benefit to epidural analgesia, but this study used general anesthesia in both arms that included inhalational anesthetics [30,31]. However, another retrospective study comparing epidural to traditional perioperative in 42,151 colon cancer patients found that, although cancer re-occurrence was not different between the two groups, the 5-year survival rate was found to favor the postoperative epidural analgesia group significantly [32]. An association has also been noted between high opioid use (≥5 mg oral morphine equivalents [OME]/day) and shorter survival in patients with advanced cancer [33]. A retrospective analysis of the influence of intra-operative analgesics on cancer recurrence following mastectomy found ketorolac decreased the risk of breast cancer relapse compared with opioid analgesics [34]. Another retrospective analysis of anesthetic management during radical prostatectomy showed a statistically significant reduction in cancer recurrence in those patients who received epidural analgesia [28]. Several mechanisms for this facilitatory effect on tumor by opiates have included modulation of the immune response or changes in cellular pathways regulating survival and metastatic behavior of the cancer cells [35] and angiogenesis [36,37].

Preclinical work has demonstrated: morphine results in decreased mitogenic activity of lymphocytes and other inflammatory cells [38–40]; enhanced tumor angiogenesis [36,37,41,42]; morphine initiates survival-promoting signaling, leading to cancer growth and metastases [36,43–46]. Conversely, negative reports have appeared showing either suppression at high doses or no effect of morphine on tumor progression [47–49] or angiogenesis [50]. In examples of tumor promotion, it is often not clear if tumor-enhancing effects are mediated through an opiate receptor. Some, but not all, of the above effects are prevented by naloxone/naltrexone [40,51] or μ-opioid receptor inactivation [46,52]. Many effects have not been so characterized. Opioid molecules (morphine) can have nonopioid receptor mediated effects, such as reduction of splenic/thymic cell number and mitogen-induced proliferation [39] and mast cell degranulation [53,54] though Mas-related genes (Mrgs) – a large family of G protein-coupled receptor [55]. Importantly, mast cell degranulation enhances proliferation of non-small-cell lung cancer cells [56]. While this observation suggests that the strategy of using a peripherally restricted opiate antagonist [46] may prove useful, it should be emphasized that mast cell degranulation by morphine is independent of an opiate receptor interaction and is not therefore affected by opiate antagonism [57].

Alternative strategies

The foregoing background commentary raises several issues: pain control must be achieved for humanitarian reasons and to avoid pain evoked changes in system function, including the inhibiting effects of pain related stress on cell mediated immunity [13,20]; increased survival after diagnosis emphasizes that cancer pain, secondary to tumor and treatment, requires correspondingly longer intervals of pain therapeutic interventions; and given the potential effects of morphine to induce tumor growth/vascularization, tumor exposure to morphine (or any μ agonist) should be avoided or diminished. This raises the potential importance of controlling pain by the use of neuraxially delivered agents where minimal systemic concentrations are obtained [16]. Thus, over the range of approximately 3–25 mg intrathecal morphine/day plasma concentrations ranged approximately 0.6–3 nM, respectively [58]. In contrast, with sustained release PO morphine at 200–600 mg PO plasma concentrations are, not unexpectedly, higher (~100–400 nM) [59].

To the degree that opioid induced hyperalgesia constitutes a problem to be avoided, and reflecting on the role of played by neuropathic pain mechanisms in the cancer itself and secondary to therapy (chemotherapeutics and radiation), perhaps other therapeutic targets, such as an sodium channel blockers (bupivacaine), α-2 agonists (clonidine) and/or N type calcium channel blockade (ziconotide), would be appropriate [60–63].

Rationale of intrathecal delivery in cancer patients

The early use of intrathecal delivery devices was limited to the treatment of cancer patients. During the 1990s, there was a transition in the use of implanted delivery systems to chronic nonmalignant pain states. However, several factors again suggest the benefits of implanted drug delivery devices in managing cancer pain secondary to tumor or therapy. First, we must consider the tenable hypothesis that tumor exposure to systemic morphine may promote tumor growth. Second, concern of the cost benefit of implanted systems led to actuarial analyses showing that the cost of implanted pumps crosses that of conventional pain therapy in 1–2 years in patients with noncancer pain [64–67]. In patients with cancer-related pain the economics can favor implantable intrathecal pumps in as little as 6 months [68]. As noted, there is now increased survival of patients after their cancer diagnosis. Third, the side effect profile is superior to systemic opiates with reduced cognitive dysfunction, a detriment to quality of life [69]. Forth, spinal opiates, because of local exposure, achieve higher receptor occupancy at the site of action in the dorsal horn and accordingly can regulate more intense pain processing. Finally, spinal delivery allows engagement of therapeutic targets which cannot be achieved systemically, as with sodium and calcium channel blockers [62]. In addition, spinal delivery of opioids results in little to no systemic levels along with improvement in the incidence of side effects in cancer patients [70]. If a pump results in significant pain relief, then to that degree the presence of potentially divertible morphine is reduced. It should be stressed that intrathecal catheters delivering morphine have several identified risks, including producing space-occupying spinal masses [60,61]. Current work appears to be progressing toward a mechanism of these masses and to providing potential alternatives [54,71].

Conclusion

There is a growing paradox within the treatment continuum between a solidifying consensus around low-dose opioid anesthesia using either intravenous anesthesia or neural blockade for cancer surgery to avoid inhibitory influences on cell mediated immunity and how the cancer patient is managed afterward. Advances in cancer therapy using new approaches, including recent advances in immunotherapy, has led to improved long-term prognoses but often patients experience cancer-related chronic pain that is treated using guidelines that are nearly 30 years old, endorsing opioids without regard to total dose as a best practice. Referrals made to pain management specialists are often too late in the course of the disease, when the patient has already been exposed to long-term and possible high-dose opioid therapy without regard to the impact they might have on a patient’s prognosis. Improvement in the prognosis of cancer patient by minimizing opioid exposure from the beginning of cancer treatment continuum and changing to intrathecal therapy much earlier in the course of the disease leading to a substantial reduction of opioid exposure has already been shown [70,72]. It is time to re-examine the entire cancer therapy continuum, with pain specialists involved from the very beginning of treatment to its conclusion.

Future perspective

The future of cancer treatment is evolving very rapidly. This evolution has occurred because cancer is no longer viewed solely as unconstrained cell division. The growing understanding of the body’s role in supporting cancer and a cancer’s ability to co-opt many of the normal processes has led to the identification of new treatment targets. Two of these newer treatment strategies include the immune system and angiogenesis. This new era of enlisting the immune system to treat cancer and the use of angiogenesis inhibitors dictates that more attention must be paid to existing treatments that have the potential risk of interfering with the effectiveness of these evolving strategies. Opioids have long been the mainstay of cancer pain treatment, yet their effects outside of analgesia are incompletely understood. Despite being effective analgesics, their ability to impact cell-mediated immunity and consequently cancer prognosis has not been systemically studied, nor is there a consensus regarding their safety in this role. There is now compelling evidence that the impact drugs have on the immune system is important and should be minimized. Alternate delivery systems for opioids such as neuroaxial analgesia and new analgesic targets must be found and clinically implemented to maximize the promise of the emerging therapeutic targets in cancer care. Pain management in the future will use these new insights that balance the need for analgesia while avoiding adverse consequences leading to loss of the new therapeutic cancer treatment potential.