FEATURE Induced Neurotoxicity

By JAN MAGNUSSON BSc (Pharm) and DR JAN MULDER BSc (Pharm) MD

GOAL therapies intended to comfort and is a condition where To educate the pharmacist on support individuals and their friends stimuli that are not normally painful opioid induced neurotoxicity (OIN) and families who are living with, or precipitate in the patient. For and its management. dying from, a progressive life threaten- example a bed sheet resting on the ing illness, or are bereaved.”(3) Comfort patients leg causes a significant INTRODUCTION care is also one of the terms used to amount of pain where normally it The pharmacist plays a key role in describe palliative care. When patients wouldn’t even be consciously noticed. monitoring the effect and adverse are enrolled on a palliative care Myoclonus is a sudden, brief, effects of medications that are taken by program it usually means that the shock-like, involuntary movement that patients. Many patients taking goals of treatment are aimed at pallia- are caused by muscle contractions. The over extended periods of time may tion of symptoms and not cure. jerks can occur singly or repetitively, have chronic progressive pain second- Palliative care does not mean that “we small (hard to detect contractions) or ary to cancer. Many of their treatments do nothing”. Many patients will want gross contractions where the limb will be for palliation rather than cure. treatment of acute reversible condi- movement can be visibly detected. Opioid induced neurotoxicity is a term tions (eg. antibiotics, blood Myoclonus can involve a single region used to describe symptoms of cogni- transfusions) if they are still experienc- or multiple regions of the body. It tive impairment, severe sedation, ing good quality of life. This often normally occurs during periods of hallucinations, myoclonus, seizures depends where they are in the trajec- drowsiness and light sleep, but is not and hyperalgesia.(1) (2) These are some tory of their illness. limited to these situations.(6) of the that we as is an area that is pharmacists should instruct the patient currently being evaluated for its rela- SIGNS AND SYMPTOMS and families to watch for. tion to N-methyl-D-aspartate (NMDA) Signs and symptoms of OIN are not always obvious. Confusion is a side DEFINITIONS effect that may be encountered for the Pain is a subjective condition. Pain Signs and symptoms of OIN are first few days-weeks when started on is what the patient tells you it is. Acute not always obvious. Confusion an opioid. This is normally mild and pain is sometimes easier to visualize self-limiting once tolerance to the on a patient’s face. There may be signs is a side effect … opioid occurs. Delirium in cancer is not of grimacing, the patient may groan always easily linked to one identifiable and cry out loud. The autonomic nerv- cause. Opioids may be the cause of the ous system may show signs of toxicity but other potential causes hyperactivity (sweating, , tachy- receptors that may be involved in the should be ruled out. (See section on cardia, and hypertension) during an pain mechanism. This type of pain is investigations). Delirium may present acute episode of pain. is due to a peripheral neurological lesion clinically either with agitated, hyperac- harder to detect at first glance. The and may be described as: burning or tive symptoms or be hypoactive. patient doesn’t show any of the auto- radiating pain, sudden episodes of Sometimes both symptoms will coex- nomic signs. Long term pain that is not shooting pain, or pain with light touch. ist.(1) relieved will cause a patient to be tired, This type of pain is often less respon- Myoclonus may be an early indica- and depressed. The patients face looks sive to typical opioids. When the dose tor that the patient is starting to sad, quiet and sleepy.(3) Assessing pain of opioid starts to escalate in the treat- develop OIN. Mild myoclonus that by visualization alone can be deceiv- ment of pain one should consider that occurs during sleep may be normal, ing. The (VAS) is this type of pain may be involved. but if the a useful tool that can provide a record Methadone can sometimes be useful in myoclonus of the patients pain history and may treating this type of pain, along with becomes noticeable Acute delirium help to show response to medication. anticonvulsants and steroids.(1) during waking Myoclonus The scale is traditionally 10cm long Treatment of neuropathic pain is hours treatment beyond the scope of this article. with numbers from 1-10. The patient options should be Seizures grades his pain at a particular time and Hyperalgesia is a term to describe a considered. If not the measurement is the patient’s pres- lowering of the pain threshold. It can treated myoclonus Hyperalgesia ent pain intensity. be a paradoxical pain where the pain can escalate into Palliative care has many different becomes overwhelming and ceases to seizures. Mild Hallucinations definitions depending on the reference. be relieved or is actually worsened by myoclonus may be In 1995 the Canadian Palliative Care further administration of the opioid.(4) observed and Table #1 Association defined it as “the combina- (5) The patient may tell you, “ I have treated with clon- Signs and tion of active and compassionate pain all over.” azepam. However, symptoms

6 COMMUNICATION MAY/JUNE 2001 when a patient is on high doses of adverse effects of narcotics. When Palliative care is best delivered by a opioids or has been on the same opioid choosing an opioid, those with shorter team of professionals who can help to for a long period of time, consider half-lives may be safer.(10) address the many issues that this rotating the opioid that the patient is Morphine is an opioid that has population of people deal with.(3) taking.(1) pharmacodynamic implications. It has Hyperalgesia, or paradoxical pain, two active metabolites; morphine-6- INVESTIGATIONS can be misdiagnosed as inadequate glucuronide (M6G) and We want to investigate looking for pain control. This may lead to increas- morphine-3-glucuronide(M3G). M6G possible underlying causes other than ing the dose of opioid. This pain is may contribute to both the analgesia opioid toxicity. One needs to check for actually caused by the opioid (a neuro- and the adverse effects observed while , dehydration, hypercalcemia, toxic side effect), and other treatments on morphine.(13) These active metabo- uremia or other metabolic changes. should be considered. (See section on lites need to be considered when a Metastatic to the brain or other treatment) patient is receiving morphine for pain organs can be ruled out by doing a Hallucinations, either visual or relief, especially if the patient is elderly bone scan, CT scan or MRI. In comfort tactile, can occur with opioids. Patients or has reduced renal function. Studies care the patient’s needs and goals of may be reluctant to relate these show in these populations that the care must come first. Expensive tests concerns to health care professionals ratios of M3G and M6G accumulate and blood work are appropriate at for fear they will be considered psychi- exponentially, making toxicity more times depending on the patient’s qual- atrically ill.(1) If the patients do not likely.(14) A case study article explains ity of life and their wishes for how verbalize their hallucinations, they that elevated concentrations of the much investigation is to be done. may be seen to pick at the air. Often metabolites may play a role in the MANAGEMENT the only signs may be a change in a development of hyperalgesia, allody- patient’s mood.(1) Family or nurses nia and myoclonus.(15) 1. Opioid Rotation who have more contact with the Meperidine is an that we Opioid induced neurotoxicity can patient will often be the source of must look at for pharmacodynamic be a result of an opioid/active metabo- information on changing mood. The considerations. It is metabolized to lites. If this is suspected then a rotation hallucinations can be managed by normeperidine which is an active to a different opioid will allow the changing or reducing opioids, or treat- metabolite. Normeperidine is a strong opioid/metabolites to be excreted and ing with medications like haloperidol. convulsant and a weak analgesic. The still maintain pain control with the problem arises because the half-life of new analgesic.(4) There is no ideal RISK FACTORS normeperidine is three-four times opioid to rotate to. The first line agents Risk factors will differ for each longer than that of meperidine. When include morphine, hydromorphone, patient. Some patients who have a normeperidine starts to accumulate fentanyl patch or oxycodone. terminal illnesses like cancer may be tremors, multi focal myoclonus and in Methadone is considered a second line on high doses of opioids or may have severe cases seizures will develop. This agent because it has an unpredictable been on them for a prolonged period opioid should not be used long term half-life and the dose is of time. There is no ceiling dose for due to these risks.(10) (12) not well documented.(1) On the positive strong opioids (i.e. morphine, hydro- Nephrotoxic medications will exac- side methadone has the benefit of low morphone etc) which allows one to erbate the renal dysfunction. NSAIDs, cost, and no active metabolites have escalate the dose as needed. Sometimes which are nephrotoxic, have been been identified yet. It is used especially this escalation may occur rapidly.(7)(8)(9) shown to be associated with increased when neuropathic pain is suspected. The pattern of opioid use to treat pain risk of myoclonus.(11) Dehydration may Methadone requires time and skill and has been changing over the years. The also be a causative factor in the emer- can only be used by those licensed to pain had been under-diagnosed gence of OIN. prescribe it. /under-treated in the past. The chang- When patients are taking a number If opioid rotation is the management ing pattern of increased use/escalating of medications the risk for drug inter- chosen, change from the current first doses has resulted in the evolution of actions increases. If patients are taking line opioid to a different first line OIN as a major side effect.(1) other CNS depressants, the sedation opioid by way of an equianalgesic Does the patient have an underly- may be additive or synergistic with conversion and reduce the dose by 30- ing condition other than the opioid opioids. Constipation caused by anti-cholinergic medications that may be causing the Infection delirium/cognition situation. The may also be additive or syner- patient may have other disease states, gistic with opioids.(10) Dehydration such as, diabetes or Alzheimers that When one is dealing with could play a role in their cognitive issues of pain control, one must Metabolic abnormalities state. remember that there are many -hypercalcemia (total Ca conc>2.60mmol/L) Opioids are metabolized by the factors that can affect the expe- -uremia liver and excreted via the kidney thus rience of pain. One needs to -hepatic encephalopathy consider the concept of “Total renal and hepatic organ dysfunction Brain Metastasis may cause opioid concentrations to Pain”. Besides the physical cause of pain, it is important to become elevated. The elevated concen- Hypoxemia-O2 and CO2 saturation levels trations may cause added central note that pain can be exacer- nervous system toxicity.(4)(10) Systemic bated by emotional, Medications-see if any can be discontinued or changed clearance of opioids is reduced in psychosocial and spiritual to medications that are less likely to cause problems patients who are older than 50 years, issues. Attention to all of these and the elderly population are more factors may play a role in our Table #2 susceptible to the beneficial and ability to treat someone in pain. Investigations

COMMUNICATION MAY/JUNE 2001 7 50% to account for incomplete cross- study, and the of the minutes to administer. It could be an tolerance. The different opioids bind to symptom. It ranges from 2.7%-87%. aid in the prevention and progression different receptors (mu, kappa, delta) Myoclonus in patients on chronic of OIN. One retrospective study looks therefor tend to have less tolerance opioid therapy seems to be dose- at doing this exam twice a week in than expected by conversion tables. related in an unpredictable manner.(21) patients with advanced cancer. The Methadone is an opioid where There are different views on the cause study compares time periods where conversion is not straight forward. of myoclonus. A deficit in serotonin cognitive assessment was completed There are several ways to convert the metabolism, an increase in release of and when it was not. If determined by patient to methadone. A detailed serotonin and interactions with other the exam that the patient’s cognitive discussion of methadone is beyond the neurotransmitter systems have been status was deteriorating, the opioid scope of this article, however there are presented to explain some types of would be rotated and hydration would references available that discuss myoclonus.(21) It has also been postu- start. They concluded that routine conversion.(3) lated that myoclonus could be caused cognitive monitoring, opioid rotation The dose reduction may be more thru an anti-glycinergic effect. Glycine and hydration may reduce the inci- than the traditional 30-50% from one is known to mediate inhibition on dence of impaired mental status opioid to another if the patient was on dorsal horn neurons. Morphine-related (OIN).(29) very high doses of the analgesic. There opioids and their metabolites may act have been reported cases where the via a spinal antiglycinergic effect to CONCLUSION patients were on very high doses of reduce post-synaptic inhibition at a The goal of the article is to educate hydromorphone and they were non-opioid receptor site, resulting in pharmacists on opioid induced neuro- switched to morphine at a dose that hyperalgesia and/or myoclonus.(8) toxicity and its management. One of was equal to ~20% of the equi-anal- If myoclonus is present, a switch or the pharmacist’s roles is to provide (7) gesic hydromorphone dose. These reduction of opioid should be consid- information on safe and effective use patients gained good pain control and ered. Symptomatic treatment may of medications. Opioids can treat were even tapered down from that include using benzodiazepines, (i.e. patient’s pain effectively but they can morphine conversion dose. midazolam, clonazepam) dantrolene, also cause serious side effects. Certain Another case describes a patient or baclofen.(6) (21)(22) (23) (24) (25) patients will be at higher risk for receiving an oral morphine equivalent 4. Psyschostimulants developing these side effects. If we are daily dosage (MEDD) of 28,000 mg per Sometimes patients on opioids can aware of the signs and symptoms and day and switching to methadone. The become sedated and drowsy. Some investigations that should be done patient’s toxicity symptoms resolved, patients with cancer can have an then we can provide optimum care to her pain was controlled and her cogni- underlying depression with or without our patients. The management of tive function improved. This patient sedation. Due to the limits of time with opioid induced neurotoxicity will vary needed intensive psycho social coun- palliative patients, traditional antide- depending on the cause. The aware- seling in addition to her medication pressants may take too long to show ness of the options will enable changes.(8) There are other case reports benefit. Psychostimulants like pharmacists to be a part of the patients available that discuss dose reduction methylphenidate, and dextroampheta- care team. greater that the traditional 30-50% mine (Ritalin and Dexedrine) are when patients are on very high anal- References available upon request to MSP useful because their onset of action is gesic doses.(9) generally quick, they will aid the A consult to a palliative or pain patient in remaining more alert, and specialist should be indicated if the help to reduce or reverse the depressed patient is not being well controlled on emotions.(26) current medications. Most studies available deal with 2. Hydration methylphenidate and the dosage range If a patient is experiencing signs is usually 2.5mg up to 80mg per day. and symptoms of OIN and is dehy- Normally the medication is given drated, hydration may be given in an twice daily, once in the morning and attempt to remove metabolites faster. the second dose at noon. Some of the Hydration in palliative care is a contro- studies available have the limitation versial area. The decision about that they don’t examine the duration of hydration may depend upon where the effect.(25) The study times are only patient is in the trajectory of their weeks, due to patients in end stage illness. Opioid induced neurotoxicity disease or that the study is slated for can make a person appear close to that duration of time.(27) (28) death. At times the use of hydration Psyschostimulants are not without side and other suggested treatments can effects. They can cause insomnia, reverse the situation and patients may anorexia, nausea, sometimes even then return to a relatively good quality delusions and psychosis. of life for a number of weeks or months. The decision should be made EARLY DETECTION on a patient to patient basis, depend- Mini-Mental Status Exam ing on the goals of care.(16)(17)(18)(19)(20) This is an easy to administer ques- 3. Myoclonus tionnaire that involves simple memory The incidence of opioid induced and recall tests. It is approximately 30 myoclonus varies depending on the questions and takes only about ten

8 COMMUNICATION MAY/JUNE 2001