‘Opioïdencrisis in USA: ook bedreigend in Europa?’

Prof. Dr. Bart Morlion

• I have interactions with the pharmaceutical industry related to the development and clinical evaluation of analgesics but receive no royalty (cash or otherwise) from sales.

• I do not own shares from these companies.

• Over the last 5 years I received grants and/or honoraria for

• Clinical research: Novartis, Pfizer, Janssen, Shionogi

• Speaker’s activities: Grünenthal, Lilly, Mundipharma, Pfizer

• Consultancy activities: Astellas, Boehringer Ingelheim, Grünenthal, Janssen, Mundipharma, TEVA, GSK, Kyowa-Kirin, Pfizer, Liilly, Boston Scientific, P&G

Disclosure Bart Morlion, MD, PhD

Today’s lecture

• Modern paradigm of pain

• Opioids in the pharmacotherapy of pain

• “Opioid crisis”

• A threat for Europe?

• Outlook

Today’s lecture

• Modern paradigm of pain

• Opioids in the pharmacotherapy of pain

• “Opioid crisis”

• A threat for Europe?

• Outlook

Figure reproduced from Fisher JP, et al. Minerva. Br Med J. 1995;310:70. 2. Associated Press, Wide World Photos. 1/16/05.

A tale of two nails !

• Complex biopsychosocial nature of pain

• Highly prevalent

• High societal impact of pain 3-10% GDP

• Chronic pain:– low efficacy of monomodal therapies

– multimodal & interdisciplinary approach

• North America: “Opioid crisis”

• Societal and political climate around “cannabis”

• Anxiety and depression, Anger, • Disturbed sleep• Kinesiophobia• Catastrophizing• Low self esteem, decreased resilience• Fatigue, Stiffness• Disturbed memory and concentration• Medical shopping, Social isolation• Substance abuse, Financial problems• Medico-legal conflicts

PAIN

Pain: Landscape & Challenges

• Chronic pain in adults: 19%

• Neuropathic Pain: 7-8%

• Low Back Pain: • Lifetime prevalence 84%

• Point prevalence 25%

• Chronic LBP: 12%

• Musculoskeletal Pain: >20%

• Migraine: lifetime prevalence 11 %

• Visceral Pain: up to 25%

• PAIN

“An unpleasant sensory and emotional experience associated with actual

or potential tissue damage, or described in terms of such damage.”1

• Alternative proposals:

• “Pain is a distressing experience associated with actual or potential tissue damage, with sensory,

emotional, cognitive and social components.” 2

• “An aversive sensory and emotional experience typically caused by, or resembling that caused by,

actual or potential tissue injury. 3

• CHRONIC PAIN

“Persistent or recurrent pain lasting longer than 3 months”

1. IASP 1994 & 20082. Williams AC, Craig KD. Updating the definition of pain. Pain. 2016;157(11):2420-33. proposed by the IASP Definition of Pain Taskforce Aug 2019.4. Treede R-D, et al. et al. Pain. 2019;160:19–27

Definitions of Pain

MG30 Chronic pain

MG30.0 Chronic primary pain

MG30.1 Chronic cancer related pain

MG30.2 Chronic postsurgical or post traumatic pain

MG30.3 Chronic secondary musculoskeletal pain

MG30.4 Chronic secondary visceral pain

MG30.5 Chronic neuropathic pain

MG30.6 Chronic secondary headache or orofacial pain

MG30.Y Other specified chronic pain

MG30.Z Chronic pain, unspecified

MG31 Acute pain

MG3Z Pain, unspecified

ICD. Available from: https://icd.who.int/dev11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f1581976053. Accessed August 2019.

ICD-11 adopted !

Persistent or recurrent pain lasting longer than 3 months

0

• Transduction

• Transmission

• Modulation

• Perception

Peripheral sensitization• Reduction threshold for nociceptor

activation

• Increase in membrane excitability

• Primary allodynia and hyperalgesia

Central sensitization• Amplification of synaptic strenghts in

nociceptive circuits• Secondary hyperalgesia

Failing descending inhibition

Spontaneous painPain hypersensitivity

Nociceptive inflammatorymechanisms

Nerve damage

Central mechanisms

Graphic composed by the author

Transition from acute to chronic pain: maladaptive neuroplasticity

Med

ical

-tec

hn

ical

Psy

cho

-So

cial

Mo

vem

ent

&

Exer

cise

Multimodallong-term and individually

Adapted from Morlion B. . Nat. Rev. Neurol. 462-473 (2013)

Management of Pain

Today’s lecture

• Modern paradigm of pain

• Opioids in the pharmacotherapy of pain

• “Opioid crisis”

• A threat for Europe?

• Outlook

Opioids NSAIDs

AtypicalAnti-neuropathic

Adjuvants

Antinociceptive herbs and spices: culinary medicine?

Pharmacotherapy of Pain: Historical Perspective

- Targeting the basic nociceptive processes1,2

- Combination of different drugs and/or routes of administration3,4

• NSAIDs• COX-2 inhibitors• Topical local anaesthetics

Transduction5

• Epidural block• Regional anaesthesia

Conduction/transmission

• Opioids5

• COX-2 inhibitors5

• Ketamine• Alpha-2-Delta

ligands5

• Alpha-2 agonists

Modulation

• Opioids• COX-2 inhibitors• Paracetamol

Perception

• Opioids5

• Antidepressants5

• NRI5

• Alpha-2 agonists

Modulation descending inhibition

1. Kumar S, et al. OA Anaesthetics. 2014;2:2. 2. Julius D, Basbaum AI. Nature. 2001;413:203-210.3. Lee B, et al. Best Pract Res Clin Anaesthesiol. 2018;32:101-111.

4. Dunkman WJ, Manning MW. Surg Clin North Am. 2018;98:1171-1184.5. Gilron I, et al. Lancet Neurol. 2013;12:1084–1095.

Multimodal pharmacotherapy of pain

• NSAIDs• COX-2 inhibitors• Topical local anaesthetics

Transduction5

• Epidural block• Regional anaesthesia

Conduction/transmission

• Opioids5

• COX-2 inhibitors5

• Ketamine• Alpha-2-Delta

ligands5

• Alpha-2 agonists

Modulation

• Opioids• COX-2 inhibitors• Paracetamol

Perception

• Opioids5

• Antidepressants5

• NRI5

• Alpha-2 agonists

Modulation descending inhibition

1. Kumar S, et al. OA Anaesthetics. 2014;2:2. 2. Julius D, Basbaum AI. Nature. 2001;413:203-210.3. Lee B, et al. Best Pract Res Clin Anaesthesiol. 2018;32:101-111.

4. Dunkman WJ, Manning MW. Surg Clin North Am. 2018;98:1171-1184.5. Gilron I, et al. Lancet Neurol. 2013;12:1084–1095.

Role of cannabinoids in the pharmacotherapy of pain?

??

?

?

• Mostly inflammatory and nociceptive mechanisms1

• Paracetamol/NSAIDs/COX-2 inhibitors/opioids1

• NNT: 1.5–2.52

• More neuropathic and nociplastic mechanisms

• Only 40–60% of patients reach 30% pain relief3

• Average improvements ranging from <10 to 20 mm VAS versus placebo4

• More atypical analgesics3,5

• Antidepressants, anticonvulsants, NMDA antagonists, opioids, α2 agonists, capsaicin, etc.

• NNT: 4–>10

COX, cyclooxygenase; NMDA, N-methyl-D-aspartate; NNT, number-needed-to-treat; NSAIDs, non-steroidal anti-inflammatory drugs; VAS, visual analogue scale

1. Moore et al. Cochrane Database Syst Rev. 2015;4:CD010794.

2. Oxford league table of analgesics in acute pain. Available at: http://www.bandolier.org.uk/booth/painpag/Acutrev/Analgesics/Leagtab.html. Accessed September 2019.

3. Dworkin RH, et al. Pain. 2007;132:237-251.

4. Dworkin RH, et al. Pain. 2011;152:S107-115.

5. Attal N, Bouhassira D. Pain. 2015;156(Suppl 1):S104-114.

6. Sabatowksi R, et al. Pain. 2004;109:26–35.

Acute pain Chronic pain

6

Pharmacotherapy of pain

HL MenckenAmerican Writer °1880-1956

For every difficult problem, there is an easy answer

short

simple

and wrong !

WHO aiming at a ‘simple’ approach to cancer pain

WHO 3-step ladder (1986)

Cancer pain relief. Geneva: World Health Organisation. 1986.

Uncritically copy-pasted for non-cancer pain !

“Our mistake is to treat chronic pain as it were acute or end of life pain”

J. Ballantyne BMJ 2016

WHO 3-step ladder (1986)

Cancer pain relief. Geneva: World Health Organisation. 1986.

Good news: update after 32 years !

WHO 3-step ladder (2018)

https://www.who.int/ncds/management/en/

My comments about“adverse effects of the WHO

stepladder”

• The sky is the limit ! = WRONG

• Limit Morphine-Equivalent-Dose 90 to 120 mg: for higher doses specialist referral recommended

• Often cancer survivors are still treated as cancer-pain patients and remain on high doses of opioids = WRONG

• Cancer survivors need the same approach as non-cancer chronic pain patients

• Uncritical use of the concept “breakthrough pain” beyond cancer pain

• Rapid-onset opioids should not be used in non-cancer pain !

Morlion B. Cited in https://www.riziv.fgov.be/SiteCollectionDocuments/consensus_lange_tekst_20181206.pdf

Today’s lecture

• Modern paradigm of pain

• Opioids in the pharmacotherapy of pain

• “Opioid crisis”

• A threat for Europe?

• Outlook

Figure 1. National Drug Overdose DeathsNumber Among All Ages, by Gender, 1999-2017

16.849

36.010

70.237

0

20.000

40.000

60.000

80.000

100.000 Total Overdose Deaths Male Female

Source: : Centers for Disease Control and Prevention, National Center for Health Statistics. Multiple Cause of Death 1999-2017 on CDC WONDER Online Database, released December, 2018

Around

192Overdose

deathsEVERYDAY

Source: : Centers for Disease Control and Prevention, National Center for Health Statistics. Multiple Cause of Death 1999-2017 on CDC WONDER Online Database, released December, 2018

Figure 2. National Drug Overdose DeathsNumber Among All Ages, 1999-2017

Source: : Centers for Disease Control and Prevention, National Center for Health Statistics. Multiple Cause of Death 1999-2017 on CDC WONDER Online Database, released December, 2018

the sharpest increase occurred among deaths related to fentanyl and

fentanyl analogs

Around

78Overdose

deathsEVERYDAY

related to illicit fentanyls

Around

47Overdose

deathsEVERYDAYRelated to

prescription opioids

Other Synthetic Narcotics other than Methadone (mainly fentanyl), 28.466

Prescription Opioids, 17.029

Heroin, 15.482

Cocaine, 13.942

Benzodiazepines, 11.537

Psychostimulants with Abuse Potential (Including Methamphetamine), 10.333

Antidepressants, 5.269

0

10.000

20.000

30.000

• 10.3 million people misused opioids in the past year

• 9.9 million misused pain relievers

• 808,000 used heroin

• 506,000 both misused pain relievers and heroin

• from 11.4 million (2017)

• 2.0 millionpeople had an opioid use disorder

• 1.7 million people with a prescription pain reliever use disorder

• 526,000 people with heroin use disorder

• 226,000 had both pain reliever and heroin use disorders

51.3%Obtained the last pain reliever they misused from a

friend or relative

37.6%Prescribed by a

healthcare provider. Only 2% received from > 1 provider

1. SAMHSA Survey 2018. Available at: https://www.samhsa.gov/data/sites/default/files/cbhsq-reports/NSDUHNationalFindingsReport2018/NSDUHNationalFindingsReport2018.pdf. Last accessed October 2019;

The state of opioid misuse in America (2018)

Opioid crisis: contributing factors

• Non- responsible prescribing• High rate of prescribing and dispensing of prescription opioids

• Pill Mills

• Aggressive marketing practices by pharmaceutical companies• Lobby to policy, patients and scientific organizations

• No rules on publicity

• Free sample policy

• Accreditation and medicolegal climate

• War on drugs !

• Socio-cultural factors, depressed economy

• Shift to illicit fentanyls

USA oxycodone consumption (mg/capita) 1980-2015

Pill Mills

Today’s lecture

• Modern paradigm of pain

• Opioids in the pharmacotherapy of pain

• “Opioid crisis”

• A threat for Europe?

• Outlook

• US population: 330 million (2019)1

• 11.4 million misuse opioids (2017) = 4.2%2

• 2.1 million with OUD3

• 70,237 drug overdose deaths (2017)1

• 47,600 overdose deaths involving any opioids1

• 17,029 overdose deaths involving prescription opioids

• Europe population: 747 million = almost 10% of the worlds population (EU: 513 million)4,5

• 1.3 million high-risk opioid users (EU)6

• 8238 overdose deaths (EU 2017)7

• Opioids found in 85% of fatal overdoses (EU)6

1. US Census Bureau. Available at: https://www.census.gov/popclock/. Last accessed October 2019; 2. SAMHSA. The National Survey on Drug Use and Health 2017. Available at: https://www.samhsa.gov/data/sites/default/files/nsduh-ppt-09-2018.pdf. Last accessed October 2019; 3. SAMHSA. An Updated on the Opioid Crisis 2018. Available at: https://www.samhsa.gov/sites/default/files/aatod_2018_final.pdf. Last accessed October 2019; 4. Worldometers 2019. Available at: https://www.worldometers.info/world-population/europe-population/. Last accessed October 2019; 5. EU 2019. Available at: https://europa.eu/european-union/about-eu/figures/living_en . Last accessed October 2019; 6. EMCDDA Statistical Bulletin 2019. Available at: http://www.emcdda.europa.eu/data/stats2019_en. Last accessed October 2019; 7. EMCDDA FAQ. Available at: http://www.emcdda.europa.eu/publications/topic-overviews/content/faq-drug-overdose-deaths-in-europe_en. Last accessed October 2019; 8. UNODC. Global Overview 2019. Available at: https://wdr.unodc.org/wdr2019/prelaunch/WDR19_Booklet_2_DRUG_DEMAND.pdf. Last accessed October 2019.

In 2017, 585,000 people died as a result of drug use worldwide, of which 167,000 died as a resultof drug use disorder8

Opioid Crisis

The percentage of Belgians on opioids

Map produced by Médor based on data of CM and RIZIV

The percentage of Belgians on tramadol in 2018

Map produced by Médor based on data of CM and RIZIV

European epidemic ? NO

• We have deaths and abuse in Europe BUT

• Ecosystem of healthcare and doctors practice differently in Europe

• Importance of monitoring

• BUT: we see higher consumption of opioids in certain countries e.g. Nordics and UK

• Recently MHRA (Medicines & Healthcare products

Regulatory Agency, UK) issued a report on the topic highlighting the issue with

opioid prescription e.g. cancer patients in remission who are still taking opioids

unnecessary are unflagged as the coding still show them as cancer patients

O’Brien T. Et al. Eur J Pain 21 (2017) 3--19 3

O’Brien T. Et al. Eur J Pain 21 (2017) 3--19 3

Clarification of medical use of opioid medications in adequately assessed and supervised patients

(1) All patients presenting with pain are adequately assessed by competent clinicians and a management strategy is devised and implemented with due regard to best international practice

(2) All prescribing clinicians are familiar with pain assessment techniques and management guidelines, including the safe and effective use of opioid medications

(3) Non-specialist prescribers must be able to refer patients for specialist opinion, that will be undertaken within a reasonable time-frame by a specialist multi-disciplinary pain team

(4) Opioids are prescribed by competent and responsible clinicians acting solely in the best interests of patient care

(5) The correct dose of any opioid is the lowest possible dose that achieves the desired clinical effect with the minimal side-effect profile

(6) If a satisfactory outcome is achieved, the patient will remain under close medical surveillance for the duration of opioid therapy

(7) Opioids, as in the case of all other medications, are initiated on a trial basis. If a satisfactory response in not achieved because of inadequate pain control and/or unacceptable bur- den of side effects, the specific opioid will be safely withdrawn and alternative options actively explored

(8) Patients and families are fully informed regarding the use and storage of opioids and are fully supported throughout the duration of therapy

(9) Opioids are dispensed by competent and responsible pharma- cists with due regard to local and national regulations and in accordance with best international practice.

(10) Patients/family members and health care professionals are expected to engage with each other in a truthful and mutually respectful manner

• 30–50% pain reduction

• Better sleep

• Better quality of life

• Maintenance of social activity

• Recovery and maintenance of ability to work

Realistic treatment goals in chronic pain management

Pain relief Side effects

Constipation

• Confusion and delirium

• Urinary retention

• Itch

• Respiratory depression

• Myoclonus

• Hormonal effects

• Immunosuppression

• Tolerance

• Physical dependence

• Addiction (0,05- 14%)

Sedation

Nausea &

vomiting

Opioid titrationDetermine a drug’s risk:benefit ratio

Taper and stop- Lack of efficacy- Non-controllable side effects

Trivedi et al. Update in Anaesthesia. 2008;1:118-124; Machelska and Celik. Front Pharmacol. 2018;9:1-22; (Voon et al. Substance Abuse Treatment, Prevention, and Policy (2017) 12:36photos by Yananya/freepik; all found at https://www.freepik.com

.Auret K, Schug SA. Drugs Aging 2005;22:641-654. Savage SR, et al. J Pain Symptom Manage 2003;26:655-667.

O’Brien T. et al. Eur J Pain 21 (2017) 3--19 3

Opioids: addiction

• Addiction is a distinct syndrome from tolerance and physical dependence. It is essentially compulsive opioid use resulting in physical, social and psychological harm.

• Addiction is characterized by one or more of the 4 Cs

• The risk of addiction developing is generally considered to be low (between 5% and 8%) and this can be dramatically reduced by screening patients for a history of previous drug or alcohol misuse.

Webster LR and Webster RM. Pain Med 2005;6(6):433

Screening for opioid misuse risk: Opioid Risk Tool (ORT)

JAMA Network Open. 2019;2(3):e190168. doi:10.1001/jamanetworkopen.2019.0168

Today’s lecture

• Modern paradigm of pain

• Opioids in the pharmacotherapy of pain

• “Opioid crisis”

• A threat for Europe?

• Outlook

Stimulating Debate

Opioids, benzodiazepines and other psychotropic drugs are often misused as “chemical coping” for

social misery and mental health care problems.

A catch-22 is a paradoxical situation from which an individual cannot escape because of contradictory rules or limitations.

https://en.wikipedia.org/wiki/Catch-22_(logic) accessed 31 JUL 2019

Outlook

• Initiation only on a trial basis: critical selection and re-assessment• Shared decision making after setting realistic treatment goals

• Informed consent about harms, including addiction, driving, endocrinopathy…

• Do not hesitate to taper and stop if goals are not met.

• Specialist care indicated for long-term prescription (>26 weeks) or high dose

• Consider drug holiday after 6 months

• Proposals:• Increase education in pain assessment and management for all HCPs

• Prescribers need insight in the prescription history!

• Identify “pill mills”

Summary

• Chronic pain is a biopsychosocial phenomenon

• Chronic pain management needs to be multimodal and multidisciplinary

• In chronic pain management effect sizes are mostly small for all pharmacological and non-pharmacological interventions

• Opioids are never the 1st choice for chronic pain management

• There is a need for rational use of opioids (lowest dose for the shortest duration) after non opioid solutions (including PT and counselling) fail in non-cancer pain

• Opioids should not be used for headache, fibromyalgia, IBS, etc.

Thank you for your attention !