Use of Methadone as an Adjuvant Medication to Low-Dose Opioids for Neuropathic Pain in the Frail Elderly: A Case Series

Abstract

Palliative care clinicians are increasingly involved in the care of elderly patients suffering from chronic malignant and nonmalignant illnesses, of which neuropathic pain is a prevalent problem. As a person becomes more frail, pain medications such as opioid analgesics and adjuvant pain medications can result in unwanted effects such as sedation, confusion, and increased risk of falls. Treating pain in patients with advanced dementia or neurodegenerative diseases that can affect swallowing is particularly challenging because most adjuvant pain medications used to ameliorate neuropathic pain must be taken orally. Furthermore, dosing of neuropathic medications is limited by renal function, which is often impaired in the elderly due to both normal aging and renal disease. Methadone is an opioid analgesic that is effective in the treatment of neuropathic pain, is excreted by the bowels, is highly lipophilic, and can be administered through the oral, buccal, or sublingual routes. We present three cases highlighting the use of low-dose adjuvant methadone to manage complex neuropathic pain in the frail elderly.

Introduction

Pain is a common issue in the elderly population. Forty percent to 80% of those living in the community and 45%–80% of those living in long-term care are affected by chronic pain.^1,2 The management of pain in the elderly poses challenges in both assessment and treatment.³ Older adults often have multiple comorbidities and are prescribed several classes of medications. In addition to the risks associated with polypharmacy, the addition of pain medications can exacerbate confusion, falls, and sedation.^4,5 Alternatively, undertreated pain in older adults can lead to mood disturbances such as depression and anxiety, decreased mobility, and a decline in cognitive function.^6,7 The WHO outlines a stepwise approach to pain management that involves the use of nonopioid analgesics for initial pain management, followed by the judicious use of opioid analgesics if pain is escalating or more severe.⁸ Adjuvant pain medications are introduced to minimize opioid dosages or to target specific pain, such as neuropathic pain that may not respond to opioids alone.⁸ Examples of adjuvant pain medications include tricyclic antidepressants, serotonin–norepinephrine reuptake inhibitors (SNRIs), and anticonvulsants. Tricyclic antidepressants are anticholinergic agents that have potential side effects in older adults such as delirium, increased risk of falls, and urinary retention. Anticonvulsants, such as gabapentin and pregabalin, and SNRIs, such as duloxetine and venlafaxine, have dose restrictions based on renal function that will affect dose titration in both patients with chronic renal disease and with renal impairment related to normal aging.

Methadone is an opioid analgesic that does not produce neurotoxic metabolites, can be titrated in very small doses, and does not depend on the kidneys for excretion. Despite literature supporting the use of methadone for complex neuropathic pain, it is rarely used in the elderly population. We present three cases of complex neuropathic pain that were managed successfully with methadone. We also examine the current literature addressing the advantages and disadvantages of using methadone in the frail elderly population.

Case 1

Mrs. G is a 94-year-old woman with moderate cognitive impairment and frailty living in long-term care. Over the past six months, she presented to the emergency department four times because of intractable back pain secondary to spinal stenosis and disc protrusion along her thoracic and lumbar spine. Over this period of time, she was prescribed increasing doses of hydromorphone along with trials of duloxetine, pregabalin, and gabapentin. However, she continued to suffer from pain and became increasingly confused or sedated.

At her most recent admission, her pain medications included Hydromorph Contin 6 mg po q12h, hydromorphone immediate release (IR) 1 mg po q4h prn, and duloxetine 30 mg po daily. She was also on quetiapine 12.5 mg po qam and 25 mg po qhs for episodes of screaming. The medical floor reported she was crying continuously and yelling that she was in pain. Repeated hydromorphone breakthrough doses did not alleviate the pain.

The palliative care team was consulted for pain management. Because her pain was poorly controlled, Hydromorph Contin was converted to hydromorphone IR 1 mg po q4h, which would allow for more precise dose titration. Her oral analgesic regimen resulted in improved pain control during the day; however, she continued to require four to five breakthroughs of hydromorphone, especially at night.

Due to her history of delirium with past introductions of pain adjuvants, the team decided to try methadone as an adjuvant pain medication. A baseline echocardiogram (EKG) showed QT interval within normal limits. Methadone was started at a dose of 0.5 mg po qhs. After three days of methadone initiation, hydromorphone IR was decreased to 1 mg po qid. Mrs. G reported improved pain control and required only one breakthrough of hydromorphone per day. Because her behaviors also improved, quetiapine was decreased to 12.5 mg po qhs. She was transferred back to long-term care where she was able to participate in communal meals and recreational group programs.

Case 2

Mr. R, an 88-year-old male was admitted to complex continuing care with a history of coronary artery disease, peripheral vascular disease with gangrene of his left foot, and a recent below-knee amputation of his right leg. He described significant neuropathic pain with sharp burning pain in his left foot and phantom limb pain at the site of the amputation.

He was treated with Hydromorph Contin 3 mg po q12h, hydromorphone IR 1 mg po q1h prn, and pregabalin 100 mg po q8h. Despite four to five breakthrough doses of hydromorphone per day, Mr. R could not achieve adequate pain relief, rating his pain as 5/10 at baseline with episodes of severe, 10/10 lancinating pain that occurred suddenly at least three times per hour. In addition, he reported unpleasant drowsiness that led to limited use of breakthrough analgesia despite significant pain. Methadone 1 mg po q12h was initiated as adjuvant pain management and Mr. R's symptoms were reviewed three days later. He reported feeling more comfortable, although he still required three to four breakthrough doses of hydromorphone per day. He denied increased somnolence with the initiation of methadone. At day 3 after initiating methadone, methadone was increased to 1 mg po q8h. Pain continued to improve with pain scores decreasing to 3/10 at rest with intermittent 5/10 shooting pain. On day 8, methadone was increased again to 2 mg po q12h. He was very comfortable on this dose and no further methadone titration was required. Mr. R was discharged to long-term care. His primary care physician applied for a patient-specific methadone license and was supported in the community by the palliative care team that initiated methadone.

Case 3

Mrs. L, a 94-year-old woman with end-stage renal disease (creatinine clearance (CrCl) of 10 mL/min) living at home, suffered from severe chronic neck pain due to a remote car accident resulting in a C5 injury. She described the pain as burning and shooting down her neck and both arms. The pain was worse with movement and caused her to stay in bed. The pain was graded as 9/10 and significantly compromised her quality of life. She exhibited signs of severe depression and was admitted to a geriatric psychiatry unit after expressing thoughts of suicidality. Once pain was identified as the likely main contributing factor to her depression and suicide ideation, the palliative care team was consulted.

Her pain medication regimen included acetaminophen 1000 mg po tid and hydromorphone IR 0.25 mg po q4h. Codeine and oxycodone were used in the past with minimal success. Gabapentin, pregabalin, and duloxetine were also used as adjuvant pain medications, but were ineffective at managing her neuropathic pain.

Given her debilitating neuropathic pain in the setting of advanced renal failure, methadone was initiated as an adjuvant pain medication. She was started on methadone 0.5 mg po q12h and her hydromorphone IR was decreased on day 2 to 0.25 mg po q8h with hydromorphone 0.25 mg po q1h prn prescribed for breakthrough pain. Her pain was rated 4/10 by day 3 of initiating methadone and her use of breakthrough hydromorphone decreased from four to two times per day, which she only took in anticipation of activity such as dressing and getting out of bed.

Over the next month, Mrs. L's renal function continued to decline and her pain increased. She was unable to return home and was transferred to the palliative care unit at the same hospital as her goals of care were comfort measures for her end-stage renal disease. Methadone was increased by increments of 0.5 mg po every three days. Adequate pain relief was achieved with a total daily dose of 2.5 mg of methadone, dosed as 1 mg po at 06:00, 0.5 mg po at 14:00, and 1 mg po at 22:00, as well as hydromorphone IR 0.25 mg po q8h. When she developed dysphagia during her final days of life, methadone was converted from tablet to liquid form for buccal administration and hydromorphone was changed to subcutaneous administration. She died comfortably on the palliative care unit.

Discussion

Methadone is a synthetic opioid that was first developed during the Second World War as an alternative analgesic that would be less addictive than morphine. Resurgence in heroin use and addiction in the 1960s prompted the investigation of methadone as a treatment for opioid dependence.⁹ Unfortunately, as a result of its association with addiction, a stigma developed around the use of methadone.¹⁰ Despite this negative perception, methadone remains a powerful analgesic and has been shown to be effective in the management of both chronic malignant and nonmalignant pain.^11,12 As a long-acting, full mu-opioid receptor agonist, it has unique pharmacological properties such as excellent oral bioavailability and no need for biotransformation to produce its analgesic effect.^12,13 Furthermore, unlike conventional opioids such as morphine and hydromorphone that can cause opioid-induced neurotoxicity due to the accumulation of active metabolites, methadone has no active metabolites.¹⁴ Methadone is excreted by both bowel and urine in most patients, but is excreted primarily by the bowel route in those with renal compromise. It differs from other commonly prescribed opioids, such as morphine, hydromorphone, oxycodone, and fentanyl, in that it also acts as an N-methyl-d-aspartate (NMDA) receptor antagonist that is thought to play an important role in the prevention of opioid tolerance, potentiation of analgesic effects, and potentially increased efficacy in the treatment of neuropathic pain.¹⁵ Additionally, methadone is low in cost and available in multiple formulations, including as an oral tablet, oral liquid, and in some countries by injection. Because methadone is lipophilic, the oral liquid formulation can be given sublingually or buccally in those who are unable to swallow.

Methadone's unique pharmacological and pharmacokinetic properties also contribute to some disadvantages compared with conventional opioids. It has a large interindividual variation in pharmacokinetics due to its long and unpredictable half-life.¹⁶ The variability in half-life has clinically significant implications because rapid dose adjustments can result in accumulation and toxicity. Methadone is also extensively metabolized by the cytochrome P450 (CYP450) system, in particular the 3A4 isoenzyme, resulting in a potentially large number of drug interactions.¹⁷ These interactions make it challenging to dose methadone appropriately in patients using medications that affect the CYP450 system (Table 1). In addition, methadone can contribute to QTc prolongation and increase the risk of Torsades de Pointes, especially at high doses (greater than 200 mg per day), or when combined with other medications that prolong QTc (e.g., quetiapine, fluconazole) or inhibit methadone metabolism.^18–20 Caution is also required when the patient is older and has other risk factors for cardiac arrhythmia (e.g., QTc above 480 ms) and metabolic abnormalities.

Table 1.

Common Drug Interactions with Methadone ^20,29

Drug	Effects	Level of evidence
Medications that are contraindicated with methadone
Buprenorphine	Opioid agonist with some antagonist effect, causing acute withdrawal effects.	Clinical studies
Medications that can decrease methadone levels
Efavirenz, nelfinavir, nevirapine, amprenavir, and ritonavir	CYP3A4 and/or CYP2B6 and/or P-gp induction.	Clinical studies
Phenytoin, carbamazepine, and primidone	CYP450 induction.	Clinical studies
Chronic alcohol use	CYP450 induction.	Published case reports
Tobacco	Possibly CYP1A2 induction.	Anecdotal reports
Medications that can increase methadone levels
Fluconazole, ketoconazole, and voriconazole	CYP3A4 inhibition.	Clinical studies (possible with other azoles)
Grapefruit	Intestinal CYP3A4 and P-gp inhibition.	Clinical studies
Selective serotonin reuptake inhibitors	CYP450 inhibition.	Clinical studies (fluvoxamine) and published case reports (others)
Macrolide antibiotics (excluding azithromycin)	CYP3A4 inhibition.	Anecdotal reports
Ciprofloxacin	CYP1A2 and CYP3A4 inhibition. Ciprofloxacin levels may be reduced by methadone.	Published case reports
Medications that can cause unforeseen effects
Tricyclic antidepressants	May increase TCA serum concentrations.	Theoretical and anecdotal case reports
Benzodiazepines	Theoretical decrease or increase of methadone serum levels through CYP450 pathways.	Published case reports

P-gp, P-glycoprotein.

When prescribing methadone, one of the biggest challenges is identifying the correct starting dose when switching from another opioid to methadone. Much of the current research revolves around identifying an equianalgesic dose of methadone to other opioids^11,21,22 and defining a protocol on how to best rotate a patient from their previous opioid regimen to methadone.^11,21–24 These two methadone conversion processes are complicated by the pharmacokinetic properties and interindividual response to methadone described previously. There are varying equianalgesic dosages depending on the original opioid dose, ranging from 3:1 when daily morphine equivalent is less than 100 mg to 20:1 when daily morphine equivalent is greater than 1000 mg.²⁵ When converting from opioids such as morphine and hydromorphone to methadone, working in close collaboration with a palliative care or pain specialist is recommended due to the complexity of a full opioid rotation.

As an alternative to a full rotation, the use of methadone as an adjuvant is an area of growing interest. By introducing methadone at small doses (as low as 0.5 mg daily) to a patient's current opioid regimen, this strategy sidesteps the concerns regarding variation in individual responses to methadone and decreases the complexity in rotating a patient from a conventional opioid to methadone.

While current literature on the use of methadone as an adjuvant is sparse, with only case reports and retrospective reviews available, the results are promising both in terms of safety and efficacy. McKenna and Nicholson reported in their retrospective study that the use of methadone as an adjuvant analgesic was effective and safe.²⁶ Methadone was introduced at a median dose of 10 mg daily (doses ranged from 2.5 to 20 mg per day) in 10 patients with severe pain alongside their existing opioid regimen and titrated according to response and adverse effects. Nine of the 10 patients reported that the addition of methadone to their regimen was very effective, and in four of the 10 cases, it was possible to reduce the background opioid after the addition of methadone. Haughey et al. reported three cases of patients with severe neuropathic facial pain from head and neck tumors, despite the use of multiple analgesics.²⁷ Methadone was introduced at low doses, 2.5–5 mg at night, and titrated to a maximum dose of 10–20 mg at night over a period of 9–15 days. All three patients experienced dramatic reductions in pain, reduced use of breakthrough analgesia, and reported minimal side effects from adjuvant methadone. Wallace et al. studied patients with moderate to severe cancer-related pain and quantitatively measured the effect of methadone as an adjuvant on the patients' pain scores.²⁸ The median methadone dose at time of initiation was 5 mg per day with the final median dose being 10 mg per day. The authors concluded that methadone was a safe, well-tolerated, and practical alternative analgesic associated with improved pain control. We contribute to the existing literature by presenting three case reports in which methadone was used in doses as low as 0.5 mg per day alongside hydromorphone to provide pain relief from chronic nonmalignant neuropathic pain.

Conclusion

Methadone is an excellent analgesic that is not used often because of its stigma and challenging pharmacological profile. However, the initiation of very low-dose methadone as an adjuvant analgesic, with its acceptable safety profile, simplifies its use and therefore the education needed to prescribe it safely and effectively. Our case reports illustrate the safe and successful adjuvant use of low-dose methadone in the frail elderly with neuropathic pain who are unable to tolerate increasing doses of conventional opioids and adjuvant pain medications. Our dose range of methadone from 0.5 to 5 mg per day was considerably lower compared with what is reported in the current literature. This reinforces the adage, start low go slow, when prescribing medications in the frail elderly. When managing difficult to treat neuropathic pain in the frail elderly, the addition of low-dose methadone as an adjuvant can be beneficial in achieving pain relief.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

References

Landi

, Onder

, Cersari

, et al.: Pain management in frail, community-living elderly patients. Arch Intern Med, 2001; 161:2721–2724.

Byrd

: Managing chronic pain in older adults: A long-term care perspective. Ann Longterm Care, 2013; 21:34–40.

Achterberg

, Pieper

MJC

, van Dalen-Kok

, et al.: Pain management in patients with dementia. Clin Interv Aging, 2013; 8:1471–1482.

Kaye

, Baluch

, Scott

: Pain management in the elderly population: A review. Ochsner J, 2010; 10:179–187.

American Geriatrics Society 2015 Beers Criteria Update Expert Panel: American Geriatrics Society 2015 updated Beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc, 2015; 63:2227–2246.

Davis

, Srivastava

: Demographics, assessment and management of pain in the elderly. Drugs Aging, 2013; 20:23–57.

Herr

, Garand

: Assessment and measurement of pain in older adults. Clin Geriatr Med, 2001; 17:457–478.

World Health Organization: WHO's cancer pain ladder for adults [Internet]. 2016. www.who.int/cancer/palliative/painladder/en/ (last accessed April 14, 2016).

Payte

: A brief history of methadone in the treatment of opioid dependence: A personal perspective. J Psychoactive Drugs, 1991; 23:103–107.

10.

Shah

, Diwan

: Methadone: Does stigma play a role as a barrier to treatment of chronic pain?. Pain Physician, 2010; 13:289–293.

11.

Bruera

, Sweeney

: Methadone use in cancer patients with pain: A review. J Palliat Med, 2002; 5:127–138.

12.

Hays

, Woodroffe

: Use of methadone in treating chronic noncancer pain. Pain Res Manage, 1999; 4:23–27.

13.

Gagnon

, Bruera

: Differences in the ratios of morphine to methadone in patients with neuropathic pain versus non-neuropathic pain. J Pain Symptom Manage, 1999; 18:120–125.

14.

Daeninck

, Bruera

: Opioid use in cancer pain. Is a more liberal approach enhancing toxicity?. Acta Anaesthesiol Scand, 1999; 43:924–938.

15.

College of Physicians and Surgeons of British Columbia: Recommendations for the use of methadone in pain [Internet].. Vancouver (BC, Canada): College of Physicians and Surgeons of British Columbia;. 2010. www.wsulibs.wsu.edu/quickguides/nlm (last accessed April 14, 2016).

16.

Davis

, Walsh

: Methadone for relief of cancer pain: A review of pharmacokinetics, pharmacodynamics, drug interactions and protocols of administration. Support Care Cancer, 2001; 9:73–83.

17.

Iribarne

, Berthou

, Baird

, et al.: Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes. Chem Res Toxicol, 1996; 9:365–373.

18.

Krantz

, Kutinsky

, Robertson

, et al.: Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes. Pharmacotherapy, 2003; 23:802–805.

19.

Ehret

, Desmeules

, Broers

: Methadone-associated long QT syndrome: Improving pharmacotherapy for dependence on illegal opioids and lessons learned for pharmacology. Expert Opin Drug Saf, 2007; 6:289–303.

20.

Beaulieu

, Beausoliel

, Comtois

, et al.: Care Beyond Cure: Management of Pain and Other Symptoms, 4e. Hospital Pharmacists' Special Interest Group in Palliative Care. Montreal: Association des pharmaciens des établissements de santé du Québec, 2009.

21.

Ripamonti

, Groff

, Brunelli

, et al.: Switching from morphine to oral methadone in treating cancer pain: What is the equianalgesic dose ratio?. J Clin Oncol, 1998; 16:3216–3221.

22.

Bruera

, Pereira

, Watanabe

, et al.: Opioid rotation in patients with cancer pain: A retrospective comparison of dose ratios between methadone, hydromorphone, and morphine. Cancer, 1996; 78:852–857.

23.

Mercandante

, Casuccio

, Calderone

: Rapid switching from morphine to methadone in cancer patients with poor response to morphine. J Clin Oncol, 1999; 17:3307–3312.

24.

Morley

, Makin

: The use of methadone in cancer pain poorly responsive to other opioids. Pain Rev, 1998; 5:51–58.

25.

Pereira

: Pallium Palliative Pocketbook, 2e. Ottawa, ON: Pallium Canada, 2016.

26.

McKenna

, Nicholson

: Use of methadone as a coanalgesic. J Pain Symptom Manage, 2011; 42:e4–e6.

27.

Haughey

. Watson M, White C: Use of methadone as a coanalgesic: Response to McKenna and Nicholson. J Pain Symptom Manage, 2012; 43:e5–e6.

28.

Wallace

, Ridley

, Bryson

, et al.: Addition of methadone to another opioid in the management of moderate to severe cancer pain: A case series. J Palliat Med, 2013; 16:305–309.

29.

Isaac

, Janecek

, Kalvik

, Zhang

(ed): Opioid Agonist Maintenance Treatment: A Pharmacist's Guide to Methadone and Buprenorphine for Opioid Use Disorder, 3e. Toronto, ON: CAMH Publications, 2015.