Opioids are the backbone of most all strategies to control cancer pain. There are three types of opiate receptors in the central and peripheral nervous systems whose role has been well established in pain management. Originally called mu, delta, and kappa, these receptors were renamed MOP, DOP, and KOP, respectively, in 2000 by the International Union of Pharmacology. There is a fourth receptor called the nociceptin receptor or NOP which, although has similar biochemical structures to the classic opioid receptors, does not appear to react to naloxone and, hence, is considered a non-opioid branch of the opioid receptor family [28].

All opioid agents act on central MOP receptors that, in turn, modulate pain by activating descending inhibition pathways. Many agents, morphine included, act on the other opiate and non-opiate receptors as well. The notorious side effects of opiate use (constipation, nausea, respiratory depression) are thought to also arise from agonizing these same receptors.

The National Cancer Institute (NCI) of the National Institutes of Health (NIH) publishes and frequently updates a comprehensive, peer-reviewed, evidence-based summary of information on pain management. Recommendations regarding pain management in this section are drawn from this important resource [29].

The goal of an opiate regimen is to achieve a steady state of analgesia with the fewest side effects, the greatest ease of administration, and at the lowest cost. Although the European Association of Palliative Care has suggested that there is little difference between full agonist opiates in terms of analgesia or side effects [30], many clinicians develop their own preferences and practices. In choosing among opiates, individual patient effectiveness and side effects, cost, presence of metabolites, underlying health conditions, and ease of administration are all important factors.

Opioid dosing can be highly variable from patient to patient and must be tailored to individual responses and characteristics. A patient who has never taken opiates before will achieve analgesia (and experience side effects) at a much lower dose than someone who has previously been exposed, either through legal prescriptions or illegal means.

A strategy for moderate or severe pain should commence with short-acting opiates given under close observation on an around-the-clock basis with a PRN rescue dose used in the case of breakthrough pain. Once a good balance between analgesia and side effects has been achieved, the total daily dose of short-acting agents can be converted to longer-acting formulations. Short-acting breakthrough opiates are still necessary and should always be available. In general, the short-acting breakthrough dose should be 10–20 % of the total daily dose given as needed every 1–4 h. Starting doses depend on the potency of the agent chosen. A strategy that starts with conservative dosing rapidly escalates to achieve pain control (for moderate pain daily increases by 25–50 % and higher for severe pain), and close monitoring of the patient for side effects, especially respiratory depression and level of consciousness, is recommended. There are no maximum doses for strong opiates.

It is often necessary to switch from one opiate to another or from one route of administration to another. For all opiates other than methadone, relative potencies are well described and calculations based upon them straightforward. The total daily (24 h) dose of the current medication is converted to the equivalent oral morphine amount. That amount is then converted to the equivalent of the new drug based upon the equivalency between it and oral morphine to determine a total 24-h dose of the new drug. This dose is then reduced from 25 to 50 % to ensure safety and then divided by the number of times in a 24-h period the new drug is given.

With rare exceptions, the best route of administration in a patient with a functioning GI tract and the ability to swallow without aspirating is oral. Rectal or transdermal routes are good alternatives; however, transdermal approaches are inadequate for acute or breakthrough symptoms. Opiates [31] should never be administered intramuscularly. If parenteral approaches are needed, IV and subcutaneous routes are equally effective. Because, however, the preparations of opiates used in these routes have greater bioavailability, the doses are one half or less than the oral equivalent. Some patients may benefit from intraspinal or intrathecal administration of opiates. In the largest randomized trial comparing intraspinal to regular pain management, pain was better relieved, there were fewer side effects, and patients lived 102 days longer [32].

Morphine is the best known and globally the most widely used full opioid agonist. It is available in both long- and short-acting formulations and can be administered via a number of routes. Like other full agonists, morphine will not reverse or antagonize other agonists administered simultaneously. It has become the “gold standard” also in the sense that potency of other opioids is measured against oral morphine. Controlled-release preparations typically have initial effect in 1 h, peak in 2–3 h, and last for up to 12 h.

Methadone, another agonist, is an attractive alternative because of its rapid oral and rectal absorption, lack of active metabolites, and low cost and availability in a liquid form. It has not been ruled out as a first-line agent for pain by the NIH expert panel. Difficulties with its use relate to its relatively erratic half-life, difficulty in determining equianalgesic levels with other opioids (the NIH consensus document outlines five different methods of determining initial methadone doses when switching from another opiate to methadone), and possible deleterious cardiac effects related to prolonged QT intervals. It should not be given in the presence of any other drugs that may prolong QT intervals. Consultation with a clinician expert who is experienced in the use of methadone is important, especially if this drug is chosen by an inexperienced provider. While it is commonly thought to have more N-methyl-d-aspartate (NMDA) receptor antagonist activity than morphine, and thus to be more effective in neuropathic pain, the only comparative randomized trial showed no major differences [33].

Short-acting preparations are appropriate for acute pain and for breakthrough or rescue dosing. Their effect usually begins within 30 min of administration and lasts for 4 h.

Fentanyl, because it can be administered transdermally, as a sublingual spray, or as a lozenge, pill, a film that dissolves orally, nasal spray, IM, or IV, can be especially useful in certain situations. A fentanyl patch is, however, not appropriate for acute pain as it takes about 12 h for the effect to start, another 12–24 h for it to peak, and generally lasts for 72 h. Fentanyl is also less absorbed in cachectic patients and required twice as high a dose as normal weight patients in one study [34]. Other full agonists that can be used in cancer pain include hydromorphone, codeine, oxycodone, oxymorphone, hydrocodone, and levorphanol.

Meperidine, which has a neurotoxic metabolite that accumulates over time, is a poor choice, especially with renal failure. Partial and mixed agonist–antagonist drugs like pentazocine, butorphanol tartrate, dezoine, and nalbuphine hydrochloride are also unsuitable because of their inherent maximum ceiling on analgesia effect. Preparations that combine an opioid with a non-opioid agent are limited by toxicities associated with the non-opioid component.

Because opiates retard gut peristalsis, stool in patients becomes dehydrated, and, unless obstruction or diarrhea is present, the patient experiences constipation. All patients taking opiates, therefore, should be given prophylaxis against constipation using, at a minimum, stool softeners. Most will also require mild osmotic agents, polyethelene glycol, and bulk-forming agents or cathartic laxatives such as senna or bisacodyl. It must be remembered that osmotic and bulk agents require oral hydration to be effective. Sennosides are the mainstay at most hospices because of effectiveness, tolerability, low cost, and there is no added effect of adding docusate to senna [35].

Nausea and vomiting often accompany use of opiates. The mechanisms responsible are stimulation of the chemoreceptor trigger zone – a dopamine-mediated event – reduced gastrointestinal motility, and, rarely, increased vestibular irritation. Metoclopramide, which can be given via oral and parenteral routes, and domperidone, which is only available orally, both improve gastrointestinal motility and have antidopaminergic effects. Consequently, these two drugs are often a first-line choice. In the United States, domperidone is not available except by special dispensation, so it is rarely used. Histamine [36]-blocking agents impact on the vomiting center and vestibular system and have their best utility when vestibular involvement is present. Haloperidol and phenothiazines are also useful, especially when motility-enhancing agents are contraindicated. Anticholinergic side effects often limit the use of chlorpromazine and anticholinergic drugs such as hyoscine hydrobromide.

Neurocognitive side effects of opioid use are not fully understood but appear, in part, to be related to opioid metabolites. Toxicities can include hallucinations, myoclonus, cognition deficits, delirium, allodynia, and hyperalgesia. In the case of a patient who demonstrates the latter symptom after starting or increasing an opiate, toxicity should be considered. Patients with renal failure or advanced disease are especially prone to neurocognitive side effects. Because morphine and hydromorphone have different active metabolites and methadone has none, clinical strategies to switch between these agents have been used to minimize neurocognitive dysfunction. A patient with cancer, especially in an advanced state, who presents with non-focal neurological symptoms of delirium or other global dysfunction, should be ruled out for side effects of other medications, dehydration, constipation, hypercalcemia, and/or sepsis.

These pharmacotherapies are used most often in conjunction with opiates to treat nociceptive pain. In some instances of neuropathic pain, however, select adjuvants can rightly be used as effective first-line therapy [37].

Nonsteroidal anti-inflammatory can serve an adjuvant role in management of cancer pain. A meta-analysis showed that single doses had a rough equivalent to 5–10 mg of intramuscular morphine. The analysis noted, however, a lack of evidence for a role in malignant bone pain. Side effects (GI bleeding, dizziness, and drowsiness) increased with dosage and showed no ceiling effect [38].

Tricyclic antidepressants (TCAs) that retard both norepinephrine and serotonin reuptake act by augmenting modulation of pain impulses at the ganglion. They make an additional contribution to pain management by treating depression itself – a state known to heighten pain perception [39]. TCA’s anticholinergic effects often limit their dosage and, hence, impact. The clinical utility of newer antidepressant agent classes, selective serotonin reuptake inhibitors, and selective serotonin–norepinephrine inhibitors, in pain management, is under investigation.

Gabapentinoids (gabapentin and pregabalin) are antiepileptic drugs that inhibit calcium release at gated calcium channels in pain pathways, depress hyperexcitability, and thus depress neurotransmission. They can be effective agents in management of neuropathic pain, work synergistically with opioids as adjuvants, and are generally well tolerated although somnolence and dizziness can limit dosage [40]. Other anticonvulsants to be considered include carbamazepine, valproate clonazepam, and lamotrigine.

Local anesthetics (mexiletine and lidocaine patch), psychostimulants (dextroamphetamine and methylphenidate), baclofen, calcitonin, clonidine, octreotide, and bisphosphonates have all been used as adjuvants in cancer pain management with varying levels of success. These are reviewed in the NCI Physician Data Query (PDQ) publication.

Corticosteroids have been widely used in managing patients with cancer pain. Aside, however, from a well-established role in managing certain types of disease (e.g., mass effect of CNS tumors and pain ensuing from increased intracranial pressure), the evidence supporting use of corticosteroids as analgesic agents is not strong and more research is needed if a firm role for them is to be adopted [41]. In one well-designed trial, dexamethasone added to metoclopramide was no better than placebo in reducing nausea [42]. Dexamethasone 4 mg bid has the added effect of improving quality of life and reducing fatigue, compared with placebo, near the end of life [43].

Tumor invasion of bony structures causes significant pain and morbidity. The clinician should be especially vigilant to identify bone pain and to rule out or address impending pathological fractures (especially if there is spinal disease and a potential for spinal cord compression). In addition to standard pain management approaches as described above, any bony involvement should prompt consideration of bisphosphonates, which are known to prevent skeletal-related events and pain in advanced breast cancer, multiple myeloma, prostate cancer, and lung cancer [44]. These drugs are also beneficial for the hypercalcemia that often accompanies advanced metastatic disease. Calcitonin has also been used to treat pain arising from cancer involving bone. A recent Cochrane review did not, however, find sufficient evidence to endorse this approach [45].

External beam radiotherapy (EBRT) is a well-documented means of addressing pain arising from bone cancer and strengthening bones damaged by tumors. A number of studies have demonstrated that single fraction therapy is equally efficacious and more cost-effective than multiple fraction therapy [46]. Radioactive particle therapy that seeks bone by binding to phosphates can relieve pain and reduce skeletal events [47], and one isotope actually prolonged survival in patients with metastatic prostate cancer [48].

Cancer-related bowel obstruction can result in significant suffering with severe symptoms and pain. In addition to standard analgesic antisecretory drugs, antiemetics and even surgical interventions (venting gastrostomy, stent, diverting ostomies, and more) are often necessary to achieve comfort. Nasogastric tubes are frequently a cause of pain themselves and should only be used on a temporary basis to relieve symptoms [49].

Advances in cancer pain management will come from a better understanding of the pathophysiology of pain, discovery of novel medications and techniques to treat pain, and smarter educational and public policies directed at promulgating pain management techniques into healthcare systems.

There are other novel ways of relieving pain that do not rely on drugs. Spinal cord stimulation, in which an electrode is positioned on the dorsal column of the spinal cord itself, can dramatically reduce pain of all types but must be performed by an experienced group using appropriate safety measures [50]. Similar techniques used for peripheral nerve stimulation have evolved over the past decade often with dramatic success, but there are no randomized comparison trials [51]. A noninvasive type of peripheral nerve stimulation using the body’s own C-fibers to conduct electrical impulses labeled as “non-pain” information is similarly promising with apparent dramatic effectiveness in cancer abdominal pain [52], cancer pain [53], chemotherapy-induced neuropathy [54], and other types of neuropathic pain; [55] randomized placebo controlled trials are ongoing.

The new and exciting technologies are not restricted to electrical stimulation. High-intensity “cold” light therapy, or photon stimulation with light-emitting diodes (LEDs), can improve some diabetic pain qualities and improve mood and quality of life compared with placebo light therapy – with just four treatments [56]. Other approaches include augmentation of microglial cells with stem cell transplantation [57], novel sodium–calcium channel blockers at the dorsal root ganglion, nerve growth factor augmentation, and a variety of other novel approaches [58].