In pelvic diseases, pain is a common and debilitating symptom with variable etiology. It can occur suddenly, sharply, and briefly (acute pelvic pain) or over the long term (chronic pelvic pain). Chronic pelvic pain refers to any constant or intermittent pelvic pain and is defined in a variety of ways. The most commonly used definitions consider both pain location and duration. In 1994, Campbell and Collett [1] defined it as “recurrent or constant pain in the lower abdominal region that has lasted for at least six months”. A similar definition was proposed by the American Congress of Obstetricians and Gynecologists: “non-cyclic pain of six or more months’ duration that localizes to the anatomic pelvis, anterior abdominal wall at or below the umbilicus, the lumbosacral back, or the buttocks, and is of sufficient severity to cause functional disability or lead to medical care” [2].

However, according to recent viewpoints, the distinction between acute and chronic pain refers not only to duration but involves the pathophysiology of the pain. While acute pain occurs in response to tissue injury to protect the body against a potentially damaging noxious stimulus, chronic pain can itself become a disease through complex mechanisms of both central and peripheral sensitization [3]. This chronic pain, also called maladaptive pain, significantly impacts the quality of life (QoL) of affected individuals, besides being very difficult to manage.

Because pelvic pain can be a symptom of most types of cancer — mostly when the cancer has progressed — and of several nonmalignant diseases, chronic pelvic cancer pain from chronic pelvic noncancer pain. Many physical nonmalignant diseases occur with chronic pelvic pain, including endometriosis, pelvic inflammatory disease, adhesions, irritable bowel syndrome, interstitial cystitis, musculoskeletal factors, and nerve-related pain. Indeed chronic non-cancer pain is very common among women, being one of the most important public health problem throughout the developed world. The epidemiology of nonmalignant chronic pelvic pain is difficult to ascertain with a true prevalence. The annual prevalence of women age 15–73 years presenting with chronic pelvic pain to primary care providers in the UK was 38/1,000. These are important data and are comparable with asthma (37/1000) and back pain (41/1000) [4, 5].

Pain in the perineal and anal region is a common feature of chronic pelvic pain in cases of malignant processes originating from the pelvis, such as locally advanced rectal cancer (LARC), or by metastatic disease. Pain control is one of many therapeutic goals throughout the duration of the disease; however, when surgery, chemotherapy, or other therapies are no longer possible to treat the underlying disease, pain control and both integrated palliative care and multidisciplinary symptom management becomes the main therapeutic target.

In pelvic and perineal cancer diseases, pain is due to several causes, such as the mass effect of lesion and chemotherapy as well as radiation and surgery. In addition to somatic pain, usually from tumor or mass effect, there is the important role of visceral and neuropathic pain, both of which are present in the majority of cases (joint pain). Visceral pain refers to the infiltration, compression, extension, or stretching of the pelvic viscera. It is not well localized and has the characteristics of deep, squeezing pressure. Neuropathic pain can arise anywhere in the central nervous system, spinal cord, or peripheral nerves as is caused by compression, infiltration, or damage to the nerves. Because pelvic cancers are particularly aggressive, with nerve damage and plexus infiltration, neuropathic pain is very intense and difficult to treat, especially after radiation therapy. Neuropathic pain can also have a chemotherapy-related component, inasmuch as these drugs (such as cisplatin, Taxol, and the vinca alkaloids) induce a peripheral neurotoxicity and subsequent painful neuropathic syndromes in patients [6] and in animal models [7]. Surgical neuropathies are well-defined syndromes. Of special interest is stump pain: a persistent postsurgical phantom pain that affects up to 18% of patients after pelvic tumor resection; it is usually severe, of stabbing, burning, pulsating, crushing and/or stinging character, and has a deleterious effect on patients’ daily functioning.

Guidelines have been developed to assist providers in assessing and treating cancer pain [8, 9]. Analgesics, particularly opioids, are the mainstay of cancer pain treatment, but a great variety of drugs available for that purpose, such as nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol, and adjuvant drugs. The World Health Organization (WHO) analgesic ladder for cancer pain management is the current recommended standard [10]. The WHO document was translated into 22 languages and has served as a catalyst for increasing awareness around the world of the importance of treating pain in cancer patients. It proposes a stepwise optimization of systemic pharmacotherapy that uses non-steroidal anti-inflammatory agents first, followed by opioid agents. More precisely, this guideline provides recommendations for analgesic selection (nonopioid, weak opioid, and strong opioid) based on pain level (mild, moderate, and severe). Tests of the analgesic ladder suggest that compliance with guidelines when using a multimodal pharmacological approach can be effective in relieving pain for up to 90% of patients [11, 12]. In any case, despite the availability of these guidelines, cancer pain continues to be inadequately managed for many patients [13].

According to WHO guidelines, the first step in pain therapy refers to “mild to moderate pain” using nonopioids, such as NSAIDs or paracetamol. While nonopioids alone usually do not provide sufficient relief for patients with pelvic cancer pain, a better result is obtained by combining adjuvant drugs with a primary indication other than pain but with some analgesic properties in some painful conditions. These medications (e.g., tricyclic antidepressants, benzodiazepines, corticosteroids, anticonvulsives) can be used alone but are usually coadministered with other analgesics, which is particularly helpful in patients with neuropathic pain. The results of a Cochrane review on nortriptyline do not support the use of this drug as a first-line treatment for neuropathic pain [14], despite duloxetine [15] and pregabalin [16] having achieved better results. The outcome of at least 50% pain intensity reduction was regarded by patients as a useful treatment outcome, and achieving this degree of pain relief was associated with important beneficial effects on sleep interference, fatigue, and depression, as well as QoL, function, and work.

Corticosteroids are commonly used to treat pain due to peripheral nerve injury or nerve/plexus infiltration and compression because it inhibits prostaglandin synthesis and decreases firing from injured nerves. With this action, pain signals diminish from the periphery to the spinal cord or from the spinal cord to the brain. Steroids also decrease capillary permeability, thereby reducing edema and the mass effect of the lesion.

Many patients with advanced pelvic cancer have moderate-to-severe chronic pain, i.e. the second step of the WHO guidelines. In this case the WHO analgesic ladder for cancer pain management advises the use of mild opioids (e.g., codeine) with or without nonopioids. Codeine is an opiate used for its analgesic, antitussive, antidiarrheal, anxiolytic, antidepressant, sedative, and hypnotic properties. While codeine must be metabolically converted to morphine by the cytochrome P450 enzyme CYP2D6, it is well known that patients who either lack that enzyme or are taking drugs that inhibit that function will get no pain relief. Medications capable of reducing, or even completely blocking, the conversion of codeine to morphine are two of the selective serotonin reuptake inhibitors, paroxetine and fluoxetine, as well as the antihistamine diphenhy-dramine and the antidepressant bupropion. Many of these drugs are often administered in cancer patients. Tramadol is a mild opioid that binds to opioid receptors with selectivity for the µ-receptor nearly 6000-fold lower than morphine. Nevertheless, a nonopioid mechanism is also involved in tramadol analgesia, consisting of enhancing the descending monoaminergic systems involved in pain inhibition. This action is achieved with the extraneural enhancement of both noradrenalin and serotonin concentration by interfering with its uptake mechanism. Codeine and tramadol can be good for mild non-cancer pain; however, cancer pain (especially pelvic cancer pain) is rarely mild enough to be managed with these drugs. Although codeine and tramadol are widely used drugs, in this situation it is possible to use strong opioids, such as oxycodone with or without naloxone; however, these drugs should be administered at the lowest effective dose.

Pelvic cancer pain is almost always “severe” pain”, and is treated using the third step of the WHO analgesic ladder, which recommends the use of strong opioids. Examples of step 3 opioids are oxycodone, morphine, fentanyl, methadone, tapentadol, and hydromorphone. Correct management of opioids drugs assumes the expertise of the provider, who must evaluate drug type, dosage, administration route, side effects, and specific pharmacokinetic phenomena, such as opioidinduced dependence and tolerance. Pain management is obtained with a case-by-case and dynamic assessment. The provider plays associating, cycling and changing different medications with different duration of action.

This potent therapy, called “around the clock” opioid therapy, is recommended by the European Society for Medical Oncology (ESMO) [17] and the European Association for Palliative Care (EAPC) as first-line therapy in patients with cancer pain to achieve sufficient pain control [18]. Oxycodone has similar efficacy to morphine (step 3), and according to ESMO and EAPC guidelines, modified-release oxycodone formulations for oral administration are an effective first-choice alternative to orally administered morphine in patients with moderate-to-severe cancer pain. Like other opioids, the primary disadvantage associated with oxycodone is the development in many patients of bowel dysfunction, which commonly manifests as significant constipation [19]. Treatment guidelines strongly recommend routine laxative use for both prophylaxis and management of opioid-induced constipation in patients with advanced cancer receiving opioid therapy. In patients who are unresponsive to laxatives, opioid antagonists, such as methylnaltrexone, are used as second-line agents to prevent and treat opioid-induced gastrointestinal effects; in in these eventualities, a fixed-dose combination opioid agonist/antagonist therapy (oxycodone/ naloxone) has been shown to preserve bowel function in patients with chronic cancer pain [20].