Patients with cancer are often more afraid of pain associated with their disease than anything else. Pain can be from the cancer itself but also from the medical and surgical treatments. Since the WHO ladder was introduced in 1986, opioids have become a centerpiece in the management of cancer pain and have done a good job managing pain in a large percentage of patients.^[1] However, 10–15% of patients do not have adequate pain control, despite maximal medical therapy. An estimated 15 million new cases of cancer per year will be diagnosed by 2020, and we need to find a better way to manage pain for those patients.^[2]

“Opioids cannot be avoided in cancer, but they need to be part of a multimodal approach to pain.”

Further, concerns are growing over problems with opioids, including tolerance, opioid-induced hyperalgesia, endocrinopathies, decreased libido, mood changes, and cognitive dysfunction associated with opioid use.^[3–5] Common side effects such as nausea, constipation, sedation, and dizziness can further limit patients' quality of life. Finally, a developing body of research is showing potential angiogenesis and tumor metastases with opioid use, likely related to the immunosuppressive, proinflammatory, and proangiogenic effects of opioids.^[6] Opioids cannot be avoided in cancer, but they need to be part of a multimodal approach to pain. The following is a review of interventional options available as part of that multimodal approach, and an argument for performing these interventions earlier in the disease course.

Celiac plexus blocks (CPB) are done for upper abdominal visceral pain, most commonly from pancreatic cancer. Pancreatic cancer often causes intractable pain not amenable to pharmacological treatment.^[7] This block was one of the first sympathetic blocks performed by pain management specialists, and recent evidence shows that earlier celiac blocks improve outcomes in pancreatic cancer. In a meta-analysis of seven randomized, controlled trials, Zhong and colleagues compared medical management to combined medical management with neurolytic CPB. CPB was associated with significantly lower pain scores at 4 weeks. In all studies except for one, pain scores were lower at 2, 4, and 8 weeks. The combined group also had significantly lower drug use and incidence of nausea and vomiting. Interestingly, the meta-analysis found that the timing of the block may influence outcomes and patients undergoing the block prior to the development of severe pain had less long-term pain and delayed onset.^[8]

Developing evidence indicates that blocks done earlier in the WHO ladder are beneficial. Amr and Makharita^[9] performed a multicenter, randomized, control trial of 109 patients receiving sympathetic blocks for abdominal and pelvic cancer before step 2 of the WHO ladder versus after step 3. The early treatment group had a greater number of block responders (p < 0.001), decreased opioid consumption in the first 12 months (p < 0.001), and improved quality of life (p < 0.05).^[9] Other studies have also shown that early treatment is associated with improved pain, decreased escalation of opioids, and delayed development of pain.^[8],[10]

Superior hypogastric plexus blocks (SHPB) are done for visceral pelvic pain from cancers of the uterus, cervix, ovaries, prostate, bladder, and rectum. Pain from these cancers is notoriously difficult to treat, because the innervation of the viscera is very heterogeneous and difficult to control with one block or one class of medications. However, Mishra and colleagues^[11] compared patients with advanced gynecologic malignancy and severe pain with medical management and combined medical management with superior hypogastric plexus neurolysis. The block group reported significantly decreased pain scores at 1 week, 1 month, 2 months, and 3 months (p < 0.05). The use of rescue morphine consumption was less at 1 week and 1 month (p < 0.05) and global satisfaction score were improved at 1 week and 1 month in the SHPB group (p < 0.001 and p = 0.04, respectively).^[11]

Ganglion of Impar (GI) blocks are done for perineal pain from cancer of the rectum, vulva, and anus, as well as metastases from other sites. It is a plexus that innervates the perineum, distal rectum, anus, distal urethra, vulva, and distal vagina. Although reports in the literature are limited mostly to case reports and case series, GI blocks consistently show improved outcomes with minimal risk of adverse effects.^[12],[13] Interestingly, in one study by Ahmed et al^[14]—a combined neurolytic GI with SHPB in 15 patients with pelvic or perineal pain—the pain scores were significantly decreased (7.87 to 2.4, p < 0.05) and oral morphine consumption decreased from 98 mg to 32 mg daily (p < 0.05). No complications or serious side effects were noted.^[14]

Peripheral nerve blocks are playing a larger role in managing cancer pain, particularly as ultrasound-guided blocks are becoming popular in both the perioperative and pain clinic settings. The role of truncal blocks, including erector spinae, serratus anterior, pectoralis nerve I and II, transverse abdominis plane, and quadratus lumborum are still being evaluated. These are particularly useful in postmastectomy neuralgias, chest wall tumors, radiation burns, and extensive abdominal surgeries with residual neuropathic and somatic pain.

Finally, neuraxial treatments continue to play a central role in managing complex pain syndromes. Epidural catheters are a useful option for managing thoracic and abdominal pain in malignancies. Because pain is expected to continue beyond hospitalization, options to prolong the epidural include tunneling epidural catheters for home infusions of local and opioids. Benefits include ease of placement and ability to target specific dermatomes. However, infection risks associated with tunneled catheters limit the option to those at the end of life.^[15]

For patients with longer expected life spans, intrathecal drug delivery systems (IDDS) can deliver opioids, local anesthetics, and adjuvants such as clonidine directly to the intrathecal space with excellent efficacy. Lower volumes are required than with an epidural; thus, patients can go for months without refilling the drug reservoir. In one randomized controlled trial by Smith et al,^[16] IDDS was compared to comprehensive medical management in 143 patients with cancer and initial visual analog scale score greater than 5. The IDDS group had more successful pain relief with more patients having a greater than 20% reduction in pain (57.7% vs 37.5%, p = 0.02). The IDDS group also had significantly less drug toxicity, including reduced fatigue and depressed level of consciousness. Interestingly, although it was not statistically significant, the IDDS patients had a trend toward improved survival, with 53.9% alive at 6 months compared to 37.2% of the medically managed group (p = 0.06).16 Other studies have also shown improved pain scores, decreased opioid use, and improved quality of life.^[17],[18] Commonly infused drugs include opioids (eg, morphine, fentanyl, hydromorphone), local anesthetics, clonidine, baclofen, and ziconotide. Another neuraxial treatment, albeit less commonly used in end-stage cancer patients, is intrathecal neurolysis. Although data consist mostly of case reports describing the technique, it has been shown to be effective for patients as a last resort as an end of life palliative treatment.^[19],[20]

These methods are a small sampling of the procedural armamentarium available to the modern interventional pain physician. Opioids will always have a role in managing cancer pain for the foreseeable future, but the opioid epidemic is shining a spotlight on what is dangerous about opioids, and the same concerns extend to using opioids in patients with cancer pain. Earlier interventions can minimize opioid consumption and improve outcomes, as shown in recent research. Although every procedure has potential risks, they must be weighed against the risks of continuing high-dose opioids and inadequate pain control. The literature in oncology and palliative care specialties is noticing the advantage of early interventions and maximizing non-opioid medications. Continuing to educate our colleagues in other specialties about what options we can offer would go a long way toward improving access to appropriate interventions for patients with cancer.

References

1. Bhatnagar S, Gupta M. Evidence-based clinical practice guidelines for interventional pain management in cancer pain. Indian J Palliat Care. 2015;21(2):137–147.
2. Frankish H. 15 million new cancer cases per year by 2020, says WHO. Lancet. 2003;361(9365):1278.
3. Crofford LJ. Adverse effects of chronic opioid therapy for chronic musculoskeletal pain. Nat Rev Rheumatol. 2010;6(4):191–197.
4. Chu LF, Angst MS, Clark D. Opioid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations. Clin J Pain. 2008;24(6):479–496.
5. Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med. 2003;349(20):1943–1953.
6. Grandhi RK, Lee S, Abd-Elsayed A. Does opioid use cause angiogenesis and metastasis? Pain Med. 2017;18(1):140–151.
7. Vissers KC, Besse K, Wagemans M, et al. Pain in patients with cancer. Pain Pract. 2011;11(5):453–475.
8. Zhong W, Yu Z, Zeng JX, et al. Celiac plexus block for treatment of pain associated with pancreatic cancer: a meta-analysis. Pain Pract. 2014;14(1):43–51.
9. Amr YM, Makharita MY. Neurolytic sympathectomy in the management of cancer pain-time effect: a prospective, randomized multicenter study. J Pain Symptom Manage. 2014;48(5):944–956 e942.
10. Wong GY, Schroeder DR, Carns PE, et al. Effect of neurolytic celiac plexus block on pain relief, quality of life, and survival in patients with unresectable pancreatic cancer: a randomized controlled trial. JAMA. 2004;291(9):1092–1099.
11. Mishra S, Bhatnagar S, Rana SP, Khurana D, Thulkar S. Efficacy of the anterior ultrasound-guided superior hypogastric plexus neurolysis in pelvic cancer pain in advanced gynecological cancer patients. Pain Med. 2013;14(6):837–842.
12. Agarwal-Kozlowski K, Lorke DE, Habermann CR, Am Esch JS, Beck H. CT-guided blocks and neuroablation of the ganglion impar (Walther) in perineal pain: anatomy, technique, safety, and efficacy. Clin J Pain. 2009;25(7):570–576.
13. Eker HE, Cok OY, Kocum A, Acil M, Turkoz A. Trans-sacrococcygeal approach to ganglion impar for pelvic cancer pain: a report of 3 cases. Reg Anesth Pain Med. 2008;33(4):381–382.
14. Ahmed DG, Mohamed MF, Mohamed SA. Superior hypogastric plexus combined with ganglion impar neurolytic blocks for pelvic and/or perineal cancer pain relief. Pain Physician. 2015;18(1):E49–E56.
15. Smitt PS, Tsafka A, Teng-van de Zande F, et al. Outcome and complications of epidural analgesia in patients with chronic cancer pain. Cancer. 1998;83(9):2015–2022.
16. Smith TJ, Staats PS, Deer T, et al. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol. 2002;20(19):4040–4049.
17. Upadhyay SP, Mallick PN. Intrathecal drug delivery system (IDDS) for cancer pain management: a review and updates. Am J Hosp Palliat Care. 2012;29(5):388–398.
18. Rauck RL, Cherry D, Boyer MF, Kosek P, Dunn J, Alo K. Long-term intrathecal opioid therapy with a patient-activated, implanted delivery system for the treatment of refractory cancer pain. J Pain. 2003;4(8):441–447.
19. Vayne-Bossert P, Afsharimani B, Good P, Gray P, Hardy J. Interventional options for the management of refractory cancer pain – what is the evidence? Support Care Cancer. 2016;24(3):1429–1438.
20. Slatkin NE, Rhiner M. Phenol saddle blocks for intractable pain at end of life: report of four cases and literature review. Am J Hosp Palliat Care. 2003;20(1):62–66.