Professor Guo Yanru: Five Major Side Effects of Opioids, One of Which Requires Special Attention!

Source: Sunflower Children Author: Professor Guo Yanru Editor: Zheng Ty Date: January 24, 2024

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Common Adverse Reactions in the Digestive System

The digestive system is the entire pathway from eating food to its final excretion from the body. Medications can cause adverse reactions within this system, including nausea, vomiting, constipation, and abdominal bloating and pain.

Nausea and Vomiting

Nausea and vomiting are common short-term side effects of opioid analgesics, occurring in about one-third of children. When managing this, doctors should follow these principles:

- Administer antiemetics on schedule as soon as symptoms appear, rather than waiting until the child is vomiting.

- Start with one antiemetic; if results are unsatisfactory, consider combining it with another different medication rather than switching between similar medications.

- Combination therapy is often more effective than monotherapy. For example, adding 5-HT receptor antagonists or scopolamine to treat nausea or using corticosteroids combined with metoclopramide and ondansetron.

Note: The specific treatment plans and dosages for all medications should be consulted with a specialist based on the child's weight and condition; self-medication is not advised.

In addition to medication, parents can help by providing a light diet, small frequent meals, avoiding foods or flavors the child dislikes, ensuring good room ventilation, and using air fresheners that the child enjoys.

Constipation

Constipation is the only adverse reaction to opioids that does not develop tolerance over time. It typically persists throughout the course of treatment and is clinically characterized by changes in bowel habits or patterns. Patients on long-term opioid therapy should be pre-prescribed laxatives.

For constipation, there are many non-pharmacological interventions. Parents can encourage their children to increase physical activity and fluid and fiber intake, which can help alleviate the issue. If constipation is severe, laxatives may be used under a doctor's guidance. It’s important to note that if the opioid dosage increases, the laxative dosage should also be adjusted according to the severity of constipation, but only after ruling out causes like intestinal obstruction by a specialist. If these methods are ineffective, opioid receptor antagonists, such as methylnaltrexone, may be considered.

Abdominal Bloating and Pain

Some children may experience increased abdominal bloating or even pain after using opioids. Parents should first check the child's abdomen for severe bloating or absence of gas and bowel movements. If these symptoms are present, a specialist must be consulted to confirm if there is an intestinal obstruction. Once obstruction is ruled out, parents can gently massage the child's abdomen clockwise, use laxatives, and, if necessary, moderately reduce food intake while increasing water consumption. Once the child resumes normal bowel movements, a gradual return to regular diet can be initiated.

Adverse Reactions in the Nervous System

Adverse reactions in the nervous system mainly include drowsiness, hallucinations, delirium, and myoclonus. Especially in terminally ill children, due to reduced food intake and metabolism, the likelihood of experiencing neurotoxicity with the same dosage of medication increases. Therefore, if neurological adverse reactions occur, the first consideration should be to reduce or even discontinue the opioid medication.

Drowsiness and Excessive Sedation

Drowsiness and excessive sedation are common short-term side effects of opioids, often seen with initial use or rapid dosage increases. Children may show decreased attention, impaired thinking, and a flat expression, with symptoms typically easing within a week of administration. If sedatives are taken concurrently or if the child has hypercalcemia or brain metastases, the incidence of these effects can increase. Some children may experience drowsiness due to previously severe pain making it difficult to sleep; once pain is controlled with opioids, they may exhibit "catch-up sleep behavior."

Preventing drowsiness and excessive sedation is crucial. If the child is particularly weak, rapid dosage increases should be avoided, and respiratory rate should be monitored to prevent respiratory depression. Some children may also experience hallucinations and myoclonus; if mild, dosage reduction or discontinuation may be appropriate, while severe cases require specialist intervention.

Delirium

The core clinical symptom of delirium is cognitive dysfunction, with an incidence of less than 5% for opioid-induced delirium. This is more common with initial use or rapid dosage increases, and the incidence can reach 20% to 90% in terminal cancer patients.

Treatment of delirium includes regulating fluid and electrolyte balance and correcting dehydration. In terminal cases, treatment often involves both pharmacological and non-pharmacological symptomatic care and safety measures. Common medications include antipsychotics, with haloperidol being the most frequently used. Other effective options include fluphenazine, risperidone, olanzapine, and quetiapine. Diazepam can have dual effects in managing and treating delirium and may be used as an adjunct; lorazepam, midazolam, and methotrimeprazine are also effective. Managing delirium necessitates the involvement of professional medical personnel, and if home care is chosen, it should be done under their guidance regarding medication and measures.

Respiratory Depression

Respiratory depression is the most dangerous side effect and the primary concern for medical staff. When opioids are used for the first time, overdose may lead to respiratory depression, but this is a tolerable side effect that usually develops tolerance after about 5 to 7 days of use without affecting analgesic efficacy, which is one reason opioids are suitable for long-term treatment.

Opioid-induced respiratory depression is primarily characterized by reduced respiratory rate (<8 breaths/min), pinpoint pupils, and the triad of coma. In most cases, this is easily identifiable. In fact, pain itself acts as a natural antagonist to respiratory depression; it will not occur until pain is under control. Even if respiratory depression does happen, it is generally not alarming; providing painful stimuli can resolve most situations. Only when pain and various stimuli are ineffective should caution be exercised in administering specific antagonists like naloxone (noting that it should be given in small, gradual doses to avoid rapid drops in opioid blood concentration leading to pain crises).

For parents, observing and managing respiratory depression can follow the "red-yellow-green" guideline:

- Green Light: The child is merely drowsy, wakes easily with a tap, and breathes evenly; monitoring is sufficient.

- Yellow Light: The child is excessively sedated and requires moderate (painful) stimuli, tapping, or conversation to awaken, but breathing remains relatively even, and pupils are not significantly constricted; close observation is necessary. If possible, supplemental oxygen can be provided at home.

- Red Light: The child exhibits clear triad symptoms (respiratory rate <8 breaths/min, pinpoint pupils, coma); medication must be stopped immediately, appropriate painful stimuli should be administered, and oxygen should be given if equipment is available. Medical personnel should be contacted promptly.

Adverse Reactions in the Urinary System

Urinary retention is a moderately tolerable adverse reaction to opioids, with a higher incidence in boys than in girls (incidence <5%). The concurrent use of sedatives increases the risk of urinary retention. In terminal treatment, non-pharmacological methods should be tried first to induce spontaneous urination; if these are ineffective, short-term catheterization may be considered.

Skin Itching

10% to 50% of patients may experience skin itching after their first use of opioids, although symptoms usually diminish after about two weeks of stable dosing. Those with dry skin can use moisturizers like petroleum jelly or lanolin, or topical antipruritics. If necessary, a doctor may consider the use of diphenhydramine. If a child’s itching is severe or persistent, switching to a different opioid may be advisable.

Tolerance ≠ Addiction

Concerns about opioid addiction are paramount for many parents. In reality, cancer pain patients using opioid analgesics long-term—especially with scheduled oral dosing—are at very low risk for developing addiction (psychological dependence).

Developing tolerance or physical dependence on opioids does not mean addiction has occurred. Tolerance refers to the reduction of adverse reactions over time, often requiring dosage increases. If opioid use is abruptly halted after long-term therapy, withdrawal symptoms may emerge, but this does not affect the safe continuation of use.

What is commonly referred to as addiction actually refers to psychological dependence, which is primarily due to improper medication use. For instance, intravenous drug administration can cause a sudden spike in blood concentration, leading to euphoria and toxic reactions, increasing the risk of addiction. The correct practice is oral administration on a schedule, which maintains stable drug concentrations and generally avoids addiction.

Addiction is characterized by at least one of the following behaviors: loss of control over use, compulsive use, continued use despite harm, and a strong craving for the drug.

For cancer pain patients, using narcotic analgesics under professional medical guidance minimizes the risk of addiction. However, patients with a history of substance abuse are at higher risk, typically observed in adults. The primary action of potent analgesics is to block pain signals in the body, and those without pain signals may misuse the medication, leading to emotional changes in the brain and resulting in psychological dependence. Thus, pain itself is a "natural antagonist" to opioid addiction.

Real-world data also show that as pain management and rational medication use increase, the global consumption of opioids for medical purposes rises without a corresponding increase in drug abuse risk.

Special Reminder

The metabolites of opioids are primarily excreted by the kidneys, so if a child has kidney dysfunction, it may lead to the accumulation of these metabolites. This is especially important with morphine and codeine, as their metabolites can accumulate and cause central nervous system depression, resulting in excessive sedation or even respiratory depression. Therefore, children with kidney dysfunction should avoid morphine and codeine and opt for medications that do not produce harmful metabolites, such as fentanyl.

Adverse reactions to opioids are mostly temporary or tolerable, except for constipation. Nausea, excessive sedation, and other adverse reactions typically occur only in the initial days of treatment and usually resolve on their own after a few days.

Preventive treatments can alleviate or avoid adverse effects from opioids. Timely administration and oral dosing are key measures to prevent serious adverse reactions.

The incidence of adverse reactions is as follows: constipation 48% > vomiting 18% > drowsiness 8% > urinary difficulties 4% > delirium 2%. Constipation, nausea, vomiting, dizziness, and drowsiness are the most common adverse reactions to opioids. Excessive sedation, respiratory depression, and urinary retention have a low incidence, often occurring in cases of combined sedation and multiple medications.

As long as opioids are used under the guidance of professional medical personnel, the risk of addiction is minimal. Rather than worrying about drug addiction, parents should focus on early identification of excessive sedation and respiratory depression, as well as how to seek help. Doctors should also assist parents and children in managing pain independently, advising them on how to obtain medications responsibly and use them safely at home.

References:

1. Expert Consensus on Adverse Reactions to Analgesics (2021 Edition)

2. Oxford Textbook of Pediatric Palliative Care, 3rd Edition

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A Message from Director Guo

The pain column comes to a temporary close here. Since the launch on World Pain Day, October 17 of last year, I have met with parents through this column every month, and unknowingly, I have written 14 installments totaling over 30,000 words.

My colleagues at Sunflower Children and I hope this column will help parents understand pain and pain medications correctly, facilitating better care for their children. We aim for no child to refuse treatment due to pain, to persevere in treatment, or to have their treatment outcomes affected.

Finally, I wish all children to defeat the little monsters soon, shining like sunflowers—bright, warm, and radiating their most beautiful smiles!

Column Author | Guo Yanru

Deputy Chief Physician, Palliative Care Department, Cangzhou People's Hospital, Hebei Province

Illustration | Wu Yuanyuan

Editor | Zuo Jia, Xia Yu

Typesetting | Xia Yu

Proofreading | Chen Zhenyu