Table 3.

Clinical studies investigating the efficacy of analgesic combination therapy in people with advance dementia

Pain medication	Authors, year, references, nationality, gradea	Population	Method	Outcomes	Findings
Paracetamol/acetaminophen, NSAIDs, oral or parenteral opioid	Hendriks et al. 2014–2015, [38, 48], NL, C	330 dying people with dementia from 34 NHs (2007–2011); 43 % had AD	2 weeks after death retrospective questionnaire to investigate association between QoL and pain	11-item QUALID; no pain tool	In the last week of life, 52 % were found to be in pain; no differences between patients between advanced and less advanced dementia; 77 % received opioids (90 mg/24 h; 88 % by injection); 43 % opioid monotherapy, 57 % opioids + paracetamol. Cannot determine the most effective treatment of symptoms
Paracetamol, morphine, buprenorphine, and/or pregabalin	Husebo et al. 2011–2014, [7, 37, 49, 50], N, A	352 NH patients with advanced dementia (type unknown) and agitation from 60 NH clusters	CRCT over 12 weeks; NH clusters were randomized to an SPTP	CMAI NPI-NH MMSE MOBID-2 Pain Scale ADL	Agitation reduced in the SPTP group (average reduction 17 % (p < 0.001, 95 % confidence interval −3.7 to −10.3) [37]. Verbally agitated behaviors, physically non-aggressive behaviors, and aggressive behaviors improved after 8 weeks (p < 0.001, p = 0.008, p = 0.037, respectively) [50]. Mood syndrome improved (p < 0.001), including depression (p = 0.025), apathy (p = 0.017), sleep (p = 0.050), and appetite (p = 0.005) [49]. Pain reduced in SPTP group compared with control (p < 0.001) at week 8, and pain scores worsened during washout (p = 0.022). Acetaminophen improved ADL function (p = 0.02) [7]

AD Alzheimer’s disease, ADL Activities of Daily Living [52], CMAI Cohen-Mansfield Agitation Inventory [86], CRCT cluster randomized clinical trial, MMSE Mini-Mental State Examination [95], MOBID Mobilization-Observation-Behavior-Intensity-Dementia [42], N Norway, NH nursing home, NL Netherlands, NPI-NH Neuropsychiatric Inventory–Nursing Home version [92], NSAID nonsteroidal anti-inflammatory drug, QoL quality of life, QUALID Quality of Life in Late-Stage Dementia [93], SPTP stepwise protocol of treating pain

^aQuality grade according to the Oxford grading of evidence