Codeine, hydrocodone, and oxycodone are available at various dosages in combination with acetaminophen, ibuprofen, or acetylsalicylic acid (ASA). Although these drugs have been shown to provide relief for cancer pain, the nonopioid components of these combination drugs are not standardized and may vary with each formulation. As a consequence, care should be taken when prescribing these drugs to patients with cancer. In the case of ASA-containing formulations, it is important to balance the potential ASA component-related benefit and the risk of major adverse renal, gastrointestinal (GI), or cardiovascular effects. Regarding acetaminophen, there is a controversy which emerged in June, 2009, after the release of the recommendations of a Food and Drug Administration advisory panel of a strong caution against combination drugs and a maximum daily dosage of 2.6 g acetaminophen owing to concerns of acute liver failure (Lee 2010). Some authors will emphasize the potential benefit of combination analgesics in terms of improve efficacy and decreased side effects in the treatment of moderate pain (Raffa 2001; O’Connor and Dworkin 2009; Markman 2010). In contrast, other publications suggest that there is no benefit to adding acetaminophen to a strong opioid treatment (Axelsson et al. 2008; Israel et al. 2010).

In either case, it is important to carefully consider the patient’s specific situation, and to not use these combined forms of drugs if the opioid dosage must be increased. Also, specific attention must be given to the patients’ compliance and education regarding their medications, especially regarding the addition of acetaminophen-containing OTC medications, including cold medications, to the combination drug.

There is limited clinical guidance regarding the initiation of opioid treatment for cancer-related pain. As reported in a recent publication, there may be no direct evidence regarding the superiority of one opioid over another, whether one should begin treatment with a short- or a long-acting form of medication, or whether patients should start with an around-the-clock dose vs. doses taken on an as-needed basis (Chou et al. 2009). However, as a rule-of-thumb, pain physicians use the maxim, “start low, go slow,” with initial treatment using immediate release forms of medication at a low dose to assess efficacy and tolerability. Also, despite the lack of sufficient evidence to support a specific titration protocol, certain evidence-based guidelines do suggest that dosage increases of 20–30% are indicated when the initial opioid dose does not give adequate pain control (Davis et al. 2004).

Titration must be done progressively, with assessments every 24–48 h. Once the pain score is decreased to three or below on a patient-reported 0–10 Likert pain scale, it is possible to switch to long-acting forms of opioids. These long-acting opioid formulations typically last 12 h and replace the initial short-acting forms; however, short-acting breakthrough opioids should be available when using long-acting drugs, and are usually prescribed at 10–20% of the 24-h total opioid dose.

Fentanyl is a synthetic opioid whose high lipid solubility facilitates the absorption through the skin and oral membranes. The transdermal delivery system (e.g., transdermal fentanyl patch) provides a consistent rate of fentanyl to the microcirculation of the skin tissue and the steady-state rate is achieved at 72 h. Patches are replaced every 3 days. The potency of fentanyl is about 100 times that of morphine (Table 17.1), and the development of fentanyl has been a major addition to the pain-control armamentarium, but the drug also has limitations. For example, due to the limitations of patch size, dosing in small increments is not possible. In addition, the long half-life of fentanyl does not allow a rapid change of dose for patients with unstable or BTP.

Targeted education must be provided to the patient regarding the use of these patches, especially given the fact that heat can cause dangerous increases to the amount of drug released and also because the drug must be disposed of in a safe manner. According to recommendations made by the European Association for Palliative Care (Hanks et al. 2001), transdermal fentanyl should be reserved for patients who require stable opioid doses or for patients unable to take oral morphine as an alternative to the subcutaneous route. An Italian survey shows, however, that fentanyl may be the first-line drug of choice for chronic pain in some situations (Ripamonti et al. 2006).

In addition to transdermal formulations, three transmucosal formulations offering various dosages have been approved for the treatment of BTP: “lozenge on the stick” (lollipops) (Actiq™), buccal effervescent tablets (Fentora™) and buccal soluble films (Onsolis™). Due to their potency and cost, these formulations must be used with caution and only in opioid-tolerant patients who receive more than the equivalent dosage of 60 mg of morphine per day and in those patients who do not respond to the usual short-acting forms of opioids (Trescot et al. 2006).

Co-analgesics (or adjuvant analgesics) are defined as medications whose primary indication is for a purpose other than the pain relief, but that also demonstrate some analgesic effects. Antidepressants and antiepileptics are first-line co-analgesics for the treatment of cancer-related neuropathic pain, as they target specific mechanisms commonly involved in this specific type of pain (Hempenstall and Rice 2002). Tricyclic antidepressants have long been the first choice therapy for neuropathic pain, and the analgesic efficacy of gabapentin has been shown in several types of nonmalignant neuropathic pain (Morello et al. 1999; Backonja et al. 1998; Rowbotham et al. 1998; Dallocchio et al. 2000; Rice et al. 2001; Backonja and Glanzman 2003). However, only a few studies assessed the efficacy of these drugs in cancer-related neuropathic pain (Oneschuk and al-Shari 2003) and often only anecdotal experience may guide the specific choice of a co-analgesic. A recent systematic review showed that a decrease in pain intensity of more than 1 point on a 0–10 numerical rating scale is unlikely with the usage of co-analgesics, while the increase in adverse events is likely (Bennett 2011).

Biphosphonates are effective in improving pain outcomes due to bone metastasis in multiple myeloma (Mhaskar et al. 2010) and in breast cancer (Pavlakis et al. 2005), though no specific biphosphonate has shown clear superiority in treating pain. Evidence for effectiveness in other cancers is limited. The use of biphosphonates may also be limited given the risk of significant adverse effects, including painful osteonecrosis of the jaw (Kahn et al. 2008).

Methadone is a μ-opioid agonist, approved for oral and intramuscular use in cancer patient. It has also been used rectally, intravenously, subcutaneously, epidurally, and intrathecally (Mandalà et al. 2006). Methadone has a number of potential advantages compared with other opioids:

Despite these substantial advantages, methadone has a long and unpredictable half-life, which makes titration difficult to achieve (Ripamonti et al. 1997, 1998) as well as large individual variations in the equianalgesic ratio of methadone to other opioids. The equianalgesic dose also varies depending on the extent of previous exposure to opioids. Caution must be exercised with methadone because of the various interactions and the potential risk of cardiac arrhythmia (Krantz et al. 2009). However, several recent studies in the palliative care cancer population have highlighted the probable safety of this potentially very useful drug (Parson et al. 2010; Reddy et al. 2010). However, more studies are warranted. Meanwhile, benefits and potential side effects of methadone must be weighed depending on the specific patient’s situation and the other options available.

The most common adverse event related to opioids is constipation, which occurs in 25–50% of patients. All patients initiating an opioid treatment should receive a laxative regimen and be provided with information on nonpharmacological approaches to constipation management such as the effects of diet and hydration on constipation.

Nausea and vomiting occur in up to 30% of patients at the initiation of an opioid treatment and antiemetics should be used as needed. Other side effects are less frequent but can be troublesome, such as pruritus and urinary retention. One of the more frightening adverse events is opioid-related toxicity, which may be caused by the effects of opioids and their metabolites in the central nervous system. Opioid-related toxicity may appear with a large variety of manifestations, such as nightmares, delirium, myoclonia, and allodynia (Mitra 2008). Careful titration and monitoring, as well as a dose reduction or opioid switch, ideally to a form without active metabolites such as methadone or fentanyl, may help avoid the development of opioid-related toxicity.

Radiation therapy can be effective in reducing cancer pain, particularly when patients’ pain derives from tumor growth. In randomized controlled trials of appropriate patients, 90% of patients received some relief and 25% a complete relief from radiation therapy, even if pain may worsen temporarily, or pain relief be delayed to up to 1 month. Several studies compared single- and multiple-fraction radiotherapy without finding differences in the effectiveness of pain relief (Foro Arnalot et al. 2008).

In terms of interventional strategies, including the use of nerve blocks, spinal (epidural and subarachnoid) administration of local anesthetics, opioids or alpha-2 agonists, spinal cord stimulation, and surgical interventions (see Zhao and Cope 2011; see also Adler et al. 2011), as dictated by patient condition, can be considered as a fourth step of the WHO Cancer Pain Ladder in patients in whom the pharmacological approach fails to achieve adequate pain relief or cause undesirable/intolerable side effects (Miguel 2000). Numerous interventional options are readily accessible and the majority can be performed on an outpatient basis. They can be used as the sole agents for the control of cancer pain or as useful adjuvants to supplement analgesia provided by opioids while decreasing opioid dose requirements and side effects. A careful risk–benefit ratio should also be considered prior to implementing invasive analgesic methods (Myers et al. 2010).

The conceptualization of pain within a biopsychosocial framework has prompted significant empirical enquiry into the potential role of psychological factors in explaining individual variability in pain response, along with pain assessment and treatment (see also Gatchel et al. 2011; Morris 2011; Hjermstad et al. 2011; Donovan et al. 2011). This has been particularly true within the domain of chronic noncancer pain, with an extensive literature now dedicated to detailing adaptive and maladaptive psychologically based factors that have been associated with this chronic condition (Keefe et al. 2004; Turk and Okifuji 2002; see also Donovan et al. 2011).

The role of psychological influences in the development and experience of cancer pain has received significantly less attention. However, this is changing, most notably in regard to chronic pain in cancer survivorship. As the number of cancer survivors in the USA increases (ACS 2010; Jemal et al. 2007; CDC 2004), there has been growing recognition of the potential long-term physical and psychological impact that treatment can exert, including ongoing pain conditions, and the need for comprehensive cancer care to be able to address such issues (Adler and Page 2007; Hewitt et al. 2005; see also Donovan et al. 2011). Psychological factors can exert an important influence across a range of pain-related behavior and treatment outcomes in cancer care. An individual’s coping style or psychological state can influence not only one’s experience of pain, but also one’s ability or willingness to report pain and accept biomedical or psychological interventions for cancer pain. The assessment and treatment of cancer pain can be particularly complex, as a patient may associate pain with disease progression, and therefore may be unwilling to report their condition accurately to their healthcare provider (Lenhard et al. 2001; see also Hjermstad et al. 2011; Dy and Seow 2011).

In both noncancer- and cancer-related pain, empirical endeavors have focused on the role of three primary psychological factors: catastrophizing, coping, and emotional distress. Although the current section examines each of these factors in turn, it is important to note that their association with pain and patient behavior remains intertwined. For example, an intervention targeting the development of adaptive coping styles may enhance a patient’s feeling of confidence in managing his/her pain, which in turn may be associated with a reduction in pain intensity or severity, along with a reduction in emotional distress. It is therefore important to recognize the complex and multidimensional nature of not only a patient’s experience of cancer-related pain but also his/her response to this pain (see also Donovan et al. 2011).

A recent report (Green et al. 2010) of evidence-based recommendations on cancer-related pain management noted that pharmacologic and nonpharmacologic interventions, including psychological and behavioral treatments, should be combined to achieve effective pain management. Likewise, guidelines state that access to and understanding of psychosocial oncology support services should be the standard of care. Although NSAIDs and opioids are generally a first-line treatment for somatic and visceral pain, currently there are no agents approved by the US Food and Drug Administration (FDA) for the treatment of neuropathic pain in cancer patients, nor have available pharmacologic treatments proven effective (Jensen et al. 2009). Further, a recent review of opioid therapies for cancer survivors noted that cognitive behavioral and physical therapies are “extremely important aspects of pain management” (Moryl et al. 2010).

Cognitive behavioral therapy (CBT) is a useful adjunctive treatment for cancer pain (see also Donovan et al. 2011). The overall goal of treatment is to provide some behavioral control over pain. Some techniques focus more on perceptual and thought processes, and some are directed at modifying behavior patterns (Breitbart et al. 2010). All approaches incorporate two basic components, (1) education regarding how thoughts, feelings, and behaviors can influence and be influenced by pain, and (2) structured training in one or more cognitive or behavioral coping skills (Cassileth and Keefe 2010). Cognitive techniques include imagery, hypnosis, restructuring of overly negative thoughts, and distraction techniques. Behavioral techniques include activity pacing, behavioral goal setting, and progressive relaxation training.

Specific techniques include relaxation, which can decrease autonomic arousal and muscular tension to decrease pain, as well as hypnosis and self-hypnosis, which can be used to manipulate perception of pain. Self-hypnosis involves using an induction (invitation to focus awareness) and one or more specific suggestions (relaxation, changing thoughts, increasing acceptance, etc.) to modify pain.

Cognitive restructuring has also been shown to decrease pain. The keys to this technique are recognizing negative cognitions (i.e., “I can’t cope with the pain”) and challenging those negative cognitions. Ultimately, patients are also taught to modify their expectations of pain (i.e., “I may not be pain-free, but I can manage the pain that I have”). This has been shown to be more effective than an education-only control condition (Ehde and Jensen 2004). Other techniques include engaging in activity pacing and distraction. Biofeedback has also been used to heighten relaxation training.

Overall, CBT has been found to be effective in individual and in group settings (Andersen et al. 2008) and has been found to have biobehavioral and immune benefits, some of which could be helpful in remediating cancer pain (Andersen et al. 2010). In addition, novel uses of CBT (i.e., MP3s of patient-controlled cognitive behavioral techniques) have been investigated and found to be feasible and well-tolerated by patients (Kwekkeboom et al. 2010).

Goals of group therapy include sharing experiences and identifying successful coping strategies. Limitations of this approach are primarily practical, in that many cancer patients experiencing significant pain and with advanced disease may not be capable of traveling to group sessions and sitting in group activities for extended periods of time. However, these interventions have been found to be quite powerful and meaningful to patients (Spiegel and Bloom 1983).

Complementary treatments are those that lie outside conventional medical treatments but are used as adjuncts to traditional medicine (National Center for Complementary and Alternative Medicine 2010; see also Kutner and Smith 2011). Complementary treatments for cancer pain include acupuncture and massage. Acupuncture stimulates the release of endogenous opioids to control pain (Carlsson and Sjölund 2001). Modern acupuncture derives from an ancient form of Oriental medicine that involves the needling and stimulation of specific anatomical points on the body. The use of acupuncture has been somewhat conflictual, with some studies finding positive results, and others concluding that the data are inconclusive. A large, randomized clinical trial found that acupuncture successfully induced analgesia in cancer patients compared to a placebo (Alimi et al. 2003). Although a recent review of the literature suggested that the evidence base continues to lack well-designed randomized clinical trials (Hopkins Hollis 2010), experimental research suggests that acupuncture analgesia is attenuated upon the administration of naloxone (Cassileth et al. 2007), which indicates an opioid-like mechanism and suggests that future research approaches should be fruitful in both clinical applications and in elucidating previously unknown mechanisms for pain control.

Massage is the practice of applying pressure, rubbing, or stroking soft tissue and skin to promote relaxation, well-being, and circulation. Reflexology massage focuses on the feet or hands, and Reiki or light touch therapies involve the gentle brushing of hands over the body. The light touch therapies are particularly helpful for patients who cannot tolerate traditional massage therapy, as is sometimes seen in cancer patients. The National Comprehensive Cancer Network (NCCN) recommends massage therapy for treatment of refractory cancer pain (National Comprehensive Cancer Network 2009). There have been concerns raised that perhaps stimulating circulation or manipulating tissue could spread metastases. Fortunately, these concerns have been disproved (Corbin 2005).

Although there are few large-scale studies in cancer, the largest study to date, involving 1,284 cancer patients, showed that massage improved pain scores for both inpatients and outpatients by 40% (Cassileth and Vickers 2004). Other, smaller studies have suggested that massage therapy increases serotonin and dopamine, as well as natural killer cells and lymphocytes, though the clinical significance of this is unknown (Cassileth et al. 2007).

Other notable interventions which have been used in a supportive role for the treatment of cancer pain include music therapy (Nilsson et al. 2005) and exercise interventions (Penedo and Dahn 2005). Exercise has been found to favorably impact mood and provide muscular, pulmonary, and cardiovascular benefits, as well as have positive effects on bodily pain reported in cancer survivors, as well as those undergoing chemotherapy treatment.

Several issues appear critical in the care of cancer-related pain as they may lead to undertreatment of pain. Specific populations at risk of undertreatment include cultural minorities, patients with earlier stage disease, those cared for at home, those with high-school education or less, (Fairchild 2010) or the elderly population, particularly women over age 65 (Cleeland 1998; see also Green 2011).

Numerous barriers for optimal pain management have been detected. These include barriers related with the patient or the patient’s support network (Morss 2010), the physician, and the healthcare system.

In regard to the patient and the patient’s support network, pain management may be hampered by poor compliance, fear of addiction or side effects (Pargeon and Hailey 1999), fear of exhausting one’s pain control options if opioids are taken too early in the disease course, fear of precipitating the disease when taking opioids, as well as drug abuse and drug diversion in the patient and the patient’s social circle. Maladaptive beliefs of all types can contribute to patient reluctance to address their pain, further suggesting a role for cognitive therapy as an adjunctive approach.

In regard to the physician, nonspecialist physicians may be reluctant to engage in cancer pain management, especially while facing complex situations, out of concern not to be able to offer the best updated medical knowledge regarding the pain control, a reluctance to prescribe Schedule II medications, the cost-effectiveness in managing a complex pain situation, and questions regarding whether patients are truly in pain or engaging in drug-seeking behavior.