1. Introduction

Most cancer patients experience pain. Many of them require opioids to relieve their pain during the course of treatment, and these compounds remain the most effective form of pain relief [1]. According to the estimates of the International Association for the Study of Pain, the prevalence of pain in all types of cancer ranges from 20 to 89% [2]. The intensity of pain varies depending on cancer subtype, treatments received, pain metric, and time since completion of oncological therapy [3]. For example, persistent pain after surgical treatment has been found to be very common in women with breast cancer. The prevalence and increasing trend of pain is higher among young patients undergoing radiotherapy and dissection of axillary lymph nodes. About 20 to 50% of women are affected by persistent neuropathic pain after surgical treatment. Prescription of opioid drugs is the treatment of choice to relieve chronic pain caused by advanced cases of cancer [4]. Various approaches for pain management and treatment are given in (Table 1). The requirement for the rational use of these drugs is careful selection of patients, correct prescription of opioid drugs, compliance with drug dosage, regular sequence of use, compliance with side effects, and drug interactions. Prescription and consumption of opioids to cancer patients are inadequate and do not have a regular pattern [7]. The effect of opioids on cancer progression, metastases, and recurrence is increasingly being questioned. In order to optimize the pain control of cancer patients, more educational and promotional measures are needed. For this purpose, the step-by-step treatment proposed by the World Health Organization is a good guide as the most appropriate standard treatment guideline for the pain of cancer patients (Figure 1). This treatment process starts with the administration of non-opioid drugs, such as paracetamol and ibuprofen. If sufficient analgesia is not achieved, weak opioids, such as codeine and tramadol, should be used. If the pain is still not properly controlled, stronger opioids, such as morphine and oxycodone, can be prescribed [9].

Approaches	Treatment
Modification of underlying pathology	Surgery, chemotherapy, radiotherapy, and hormone therapy.
Pharmacotherapy	Nonsteroidal anti-inflammatory drugs, anticonvulsants, opioids, antidepressants, and corticosteroids.
Interventional techniques	Local anesthetics and neurolytic agents
Non-opioids	Paracetamol, acetyl salicylic acid, indomethacin, ibuprofen, diclofenac, and naproxen.
Weak opioids for mild to moderate pain	Codeine, tramadol, and dihydrocodeine
Strong opioids for moderate to severe pain	Morphine, methadone, and oxycodone

Table 1.

Different approaches to cancer pain management [5, 6].

Figure 1.
WHO’s analgesic ladder for relief of cancer pain [8].

The purpose of this review was to examine the reasons and current status of prescribing and consuming opioids in patients with advanced cancer and to provide solutions to rationalize this process.

2. Methods

In this chapter, we will discuss the prevalence of chronic cancer pain, the therapeutic use of opioids, the effectiveness of treatment with this class of therapeutic compounds, guidance for the responsible and consistent administration of opioids for patients with chronic cancer, associated outcomes, and the challenges of managing patients with chronic cancer pain. The comprehensive literature search was conducted for the period 2004 through June 2023. Databases for this purpose included PubMed, EMBASE, Cochrane reviews, and clinicaltrails.gov along with reviews and cross-references. Keywords in this search focused on opioid therapy in the management of cancer-related pain. All studies were independently screened and reviewed by the authors based on their titles and abstracts. The full text of articles potentially suitable for review was assessed.

3. Opioids

3.1 Pharmacology aspects

As mentioned, opioid therapy is often used to control pain in most cancer patients during their disease course. Opioids are the cornerstone of pain management in cancer treatment, and their use has been increasing in recent years. Cancer pain is usually effectively treated by administering opioids at regular intervals and providing effective doses to manage pain failure [9]. No specific opioid will be prescribed for all patients. It is possible to optimize the effect of an opioid for any manifestation of the disease [10, 11]. Specialists are not able to predict the exact treatment response of patients. After the initial opioid administration, its clinical effectiveness may decrease gradually over time or even suddenly, resulting in the need to increase the dose. In some cases, increasing the dose does not cause pain relief and may even cause side effects [12, 13].

The proper administration of opioids, considering their wide range, requires a deep understanding of the pharmacology and pharmacokinetics of these different analgesics. Opioids cause analgesia by acting on receptors located in the membrane of nerve cells. Their main effect in the nervous system is the presynaptic effect in inhibiting the release of neurotransmitters [6]. There are three types of opioid receptors, including m, d, and k (mu, delta, and kappa) [7]. Understanding the molecular structure of opiate receptors will lead to the provision of more accurate approaches in the study of opioid pharmacology (Figure 2). Opioid receptors are found throughout the body, mainly in the brain, spinal cord, and intestinal tract. These receptors consist of complex structures of seven amino acid chains, each of which is placed on the membrane and forms a channel that can allow calcium ions to pass inside or outside the neuron [9]. Pharmacological studies have shown that the interaction of the natural opioid-like peptide, b-endorphin, is preferentially with m-receptors, enkephalins with d-receptors, and dynorphin with k-receptors (Table 2). The affinity of morphine is more concentrated at m-receptors compared to other opioid receptors. The opioid antagonist naloxone results in the inhibition of all opioid receptors, but its greatest affinity is focused on m-receptors. By connecting an opioid substance to each of these three types of receptors, they cause analgesia. Activation of k- receptors does not cause physical dependence as much as activation of m-receptors [7, 19]. Pure opioid agonists, such as morphine, hydromorphone, and fentanyl, stimulate μ-receptors and are considered to be the strongest pain relievers. Opioids with different potency may react with N-methyl-D-aspartate (NMDA) receptors and activate the descending pain pathways of serotonin and noradrenaline from the brainstem. Stimulation of these NMDA receptors may lead to neuropathic pain and tolerance [20, 21, 22].

Figure 2.
Opioid receptor structure [14].

No	Design	Regular opioids	Severe adverse effects	Follow-up	Ref.
1	A prospective survey of inpatients and outpatients on regularly dosed morphine	Morphine	Dry mouth, sedation, and constipation were frequent, nausea, Myoclonus.	4 weeks	[15]
2	An observational study	Tapentadol and oxycodone/naloxone	Higher rates of erythema and vomiting, especially in females.	–	[16]
3	A prospective, real-world, and multinational study	Naloxegol	Treatment-related adverse events were mainly gastrointestinal events, the most frequently reported being abdominal pain and diarrhea.	4 weeks	[17]
4	A prospective single-center observational study	Nalbuphine and Morphine	Nalbuphine therapy was accompanied by a statistically significantly lower incidence of side effects such as skin pruritus, constipation, and micturition disorders compared to morphine (p < 0.05).	Two years between March 2019 and March 2020.	[18]

Table 2.

Summary of published opioids-based side effects studies on cancer pain.

3.2 Common opioid analgesics in cancer pain relief

This work summarizes the current knowledge regarding the impact of common opioids in cancer pain progression with an emphasis on clinical outcomes (Figure 3).

Figure 3.
Common opioid compounds during clinical use [7, 9].

3.2.1 Morphine

Morphine is still used as one of the most common pain relievers and cancer pain relievers. Morphine affects the u- and κ-receptors, but its analgesic effect is mainly carried out by the u-receptors [7, 9]. In a randomized, multicenter, and open-label trial at a Japanese hospital’s palliative care service, Matsuoka et al., evaluated the potential of the opioid choice in cancer pain management using a catechol-O-methyltransferase (COMT) genotype biomarker. They demonstrated that the proportion of patients requiring high-dose opioids was significantly higher in the morphine group when compared with the oxycodone group in those with the COMT-rs4680 GG genotype [23]. Wasan et al., stated that hydromorphone was present in 66% of morphine users without aberrant drug behavior. This proves that morphine is metabolized to codeine and hydromorphone in small amounts. This process usually occurs with doses higher than 100 mg per day [24].

3.2.2 Codeine

Codeine is known as a prodrug and a weak opioid. Generally, this opioid is prescribed after surgery and is used along with specific medications to manage acute and chronic pain. Its administration is not recommended in the presence of renal failure. Codeine administration in children had low clinical effectiveness and has not shown a significant response with increasing the dosage [9]. Ou et al., stated that short-term use of tramadol compared with codeine did not lead to an increased risk of cardiac events among patients with non-cancer pain [25]. Limited literature were found on the effect of codeine on the process of pain management in cancer patients. In this line, Straube et al., investigated the efficacy and safety of codeine used alone or in combination with paracetamol for relieving cancer pain. Overall, codeine or codeine plus paracetamol was numerically superior to placebo groups and equivalent to active comparators [26].

3.2.3 Hydrocodone

Like codeine, it has been proposed that hydrocodone is a prodrug used in patients with advanced cancer. Today, hydrocodone is available as an extended-release with side effects similar to other opioids. This opioid is a suitable option for children who have a poorly metabolized phenotype [27].

3.2.4 Hydromorphone

The structure of hydromorphone is similar to morphine, and it is available in both oral and injectable forms [27]. Its high potency and solubility may be useful for patients who require high doses of opioids injected subcutaneously [9]. In a review study, Li et al., stated that hydromorphone to work as well as morphine, oxycodone, and fentanyl and appears to be an alternative opioid analgesic, which may help relieve pain symptoms for people with advanced cancer. This review includes a total of eight studies, which compared hydromorphone with oxycodone, morphine, and fentanyl. They found no clear evidence of a difference in nausea, vomiting, and dizziness in persons treated with hydromorphone compared with those treated with morphine [28]. The evidence is very uncertain and no studies reporting quality of life. Also, these studies did not include children.

3.2.5 Fentanyl

Fentanyl is approximately 80 times more potent than morphine, and as a highly lipophilic opioid is used for relieving cancer pain in transdermal and transmucosal immediate-release formulations [7]. Fentanyl undergoes extensive metabolism in the liver and binds strongly to plasma proteins. It is one of the most commonly used analgesics among pediatric patients. Fentanyl can be administered by continuous intravenous or subcutaneous infusion [9]. Thantiprechapong et al., evaluated the efficacy of reconstituted intravenous rapid-acting fentanyl formulations to sublingual solution versus oral morphine for breakthrough pain among patients with chronic gynecologic cancer pain. The primary outcome was the reduction in early breakthrough pain with administration of intravenous fentanyl to sublingual solution. Intravenous fentanyl to sublingual solution may be considered for breakthrough pain when rapid-acting fentanyl formulations are unavailable [29].

3.2.6 Sufentanyl

Sufentanyl is injected into cancer patients as an alternative to fentanyl under certain conditions. A lower dose of sufentanyl is effective for pain control among patients, especially those with renal failure [27]. Tan et al., investigated the postoperative effects of sufentanil preemptive analgesia combined with psychological support therapy on breast cancer patients undergoing radical surgery. Overall, they concluded that prophylactic analgesia with sufentanil administration along with psychological support is an effective method of pain relief for breast cancer patients undergoing radical surgery. This technique deserves to be promoted in the clinic [30].

3.2.7 Methadone

Methadone as a synthetic opioid with highly variable pharmacokinetics is commonly used as a second-line option in the presence of neuropathic pain in cancer. Its average half-life ranges from less than 15 hours to more than 130 hours. The analgesic effect of methadone is more stable than that of morphine. Due to the limited researches in the field of methadone use, the effective dose of this opiate is still a challenging issue and needs to be started, adjusted and carefully monitored during the treatment of cancer patients [31]. In this line, Furst reviewed the current knowledge of low-dose methadone treatment in palliative cancer care. He stated that methadone use requires an experienced physician and solid follow-up. Continuous administration of low-dose methadone has been shown to be effective and safe in reducing pain in dying patients without increasing confusion, regardless of age [32]. Although the available data are not sufficient to draw a final conclusion, observational and controlled studies in the administration of other strong opioids have shown that methadone is a valuable drug even as the first choice in steps two and three of the analgesic ladder.

3.2.8 Levorphanol

Similar to methadone and morphine, levorphanol is an effective treatment for chronic neuropathic pain. Levorphanol has a shorter plasma half-life with a more prolonged duration of action compared to methadone and may have a substantially lower medication accumulation risk [9, 27]. There are no well-known and extensive studies on the effectiveness of levorphanol in cancer patients, and current evidence is not insufficient to support its use in many pain situations. Reddy et al., determined the proportion of successful opioid rotation from morphine equivalent daily dose to levorphanol in cancer patients with successful opioid rotation. The obtained preliminary data showed that cancer patients could be successfully rotated to levorphanol using an opioid rotation ratio of 8.5. Levorphanol administration was associated with improvement of pain and disease symptoms control and was well-tolerated [33].

3.2.9 Buprenorphine

Buprenorphine has been used for many years to relieve acute pain and more recently to treat opioid addiction and relieve chronic pain. It has a high affinity for the u-receptor and is used for managing cancer pain with conversion to an active metabolite called norbuprenorphine, which is a weaker but full-opioid agonist [9, 27]. Shen et al., monitored the effects of transdermal buprenorphine on quality of life and some effective symptoms in cancer patients with pain in Asian populations. The preliminary evidence from the administration of transdermal buprenorphine showed an improvement in the quality of life and a reduction in the severity of symptoms and pain in Asian patients with cancer [34].

3.2.10 Oxycodone

Oxycodone is an oral and semisynthetic opioid used to relieve cancer-related pain. Administration of oxycodone was more effective in reducing pain intensity than other strong opioids and resulted in fewer side effects, indicating a better effect of this drug in pain relief in cancer patients [20]. King et al., reviewed the quality of evidence for the use of oxycodone in the relief of cancer pain in adults. There was no evidence of a significant difference in analgesia or side effects between oxycodone and either morphine or hydromorphone. Therefore, oxycodone can be used as a suitable alternative to morphine or hydromorphone in cancer-related pain [35]. In this line, Weme et al., evaluated the potential drug-drug interaction of enzalutamide and oxycodone in men with prostate cancer. Co-administration of enzalutamide showed a significant decrease in exposure to oxycodone and its active metabolite oxymorphone, which should be considered when prescribing enzalutamide with oxycodone [36].

3.2.11 Tramadol

Tramadol is recommended for cancer patients with moderate to severe pain when other opioids are ineffective. Tramadol contains two enantiomers and a synthetic analog of codeine and morphine, both of which increase analgesic properties through different mechanisms [37]. Tuan et al., evaluated the role of tramadol/dexketoprofen fixed-dose combination in management of patients with moderate-to-severe acute cancer pain. The pharmacological synergism between tramadol and dexketoprofen along with the environmental effect compared to the use of each of these medicinal compounds alone will lead to an increase in analgesic activity in lower doses and with better tolerance [37].

3.2.12 Tapentadol

Tapentadol is structurally similar to tramadol and is used to relieve severe chronic pain in cancer patients [9]. Boland et al., suggested that tapentadol as an effective pain reliever can be used as an alternative to morphine and oxycodone, especially during opioid poisoning [38]. In a prospective, multicenter, open-label study, Jung et al., monitored the clinical efficacy of tapentadol on pain control and the quality of life of patients with moderate to severe chronic cancer pain in clinical practice in Korea. They stated that tapentadol extended-release was effective for treating patients with moderate to severe cancer pain and neuropathic pain, and therefore it significantly improved the patients’ quality of life [39].

3.3 Opioid routes of administration

Opioids should be administered in the least invasive and safest way possible to achieve satisfactory analgesia. Oral administration is preferred over other routes because of its convenience, relative safety, and cheapness. An accepted alternative for long-term treatment is the use of the transdermal route [7, 9]. Some of the most important routes of opioid administration are shown in (Figure 4).

Figure 4.
Opioid routes of administration [7, 9, 27].

3.4 Mechanism of action in pain relief

Major recent advances in understanding the mechanism of action of opioids include the cloning and identification of opioid receptors (opioid receptors), understanding the cellular function of opioids, and identifying the sites of opioid action in the brain. With the activation of the receptor, the protein released inside the cell leads to the activation of Na/K channels and affecting intracellular enzymes or nuclear gene transcription [9]. Opioid receptors can be presynaptic or postsynaptic. Presynaptic opioid receptors inhibit the release of neurotransmitters acetylcholine, norepinephrine, and serotonin [7].

3.5 Factors influencing outcomes

Studies have shown that factors, such as age, gender, pain syndrome, and the use of auxiliary drugs, did not affect the need for opioids or their replacement. This is while underlying diseases such as kidney failure along with the use of certain drugs caused a change in opioids and their effective dose in pain relief [19]. The results in this field are somewhat contradictory.

3.6 Risks and side effects

As with any potential therapy, opioids carry risks and adverse effects. The use of opioids causes various side effects at the same time as the administration of chemotherapy drugs, most of which include nausea and vomiting, constipation, and depression [7, 27]. In some circumstances, some patients avoid opioids because of these side effects, which may act as an important barrier to complete pain relief (Table 2).

4. Conclusions and future perspective

Pain relief guidelines have been developed to care for patients after surgery and improve their quality of life. Cancer patients usually undergo chemotherapy, which can be painful and uncomfortable. Therefore, patients need to use opioids. It is very important to have correct information about the patient’s pharmacogenomics during pain management and medical care. In order to optimize research in this field, prospective studies should include experimental designs, randomized and controlled clinical trials on cancer pain patients receiving opioids and control patients. Others include pre- and posttreatment assessments, adequate sample sizes, and neuropsychological testing that can be related to opioid use. Examination of patient quality of life, mechanisms by which different opioids may affect cognition, opioid switching/rotation, short-acting opioids on demand, individual differences/characteristics/genetics, emotional factors, and other symptoms should not be overlooked. Switching from one opioid to another may be problematic, especially when using high doses. Unpredictable conversion rates depend on many individual and clinical variables. Some opiates, such as methadone, are suitable compounds due to their much lower cost, which is a great advantage in developing countries. Of course, in the use of these compounds, attention should be paid to their pharmacokinetics as an increase in the risk of accumulation and delayed toxicity, apart from the potential for this compound to interact with other drugs. The limitations of the studies used and sometimes their quality are obvious limitations in writing this chapter. In addition, there is limited information on dose titration methods for each opioid. The concern of using these compounds in the pediatric population and people with underlying diseases can be an interesting indication that is worth future research. Further studies with appropriate design should provide information on the long-term use of opioids with the previously mentioned details.

Conflict of interest

The authors declared no conflict of interest.

Haruka Suzuki

Chapters authored

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